JP2006527262A - Cannabinoid receptor ligands and uses thereof - Google Patents

Abstract

Described herein are compounds of formula (I) or (II) that act as cannabinoid receptor ligands and their use in the treatment of diseases associated with modulation of cannabinoid receptors in animals.

Description

TECHNICAL FIELD OF THE INVENTION The present invention treats substituted pyrazolopyridazine and imidazopyridazine compounds as cannabinoid receptor ligands, in particular CB1 receptor antagonists, and diseases, conditions and / or disorders modulated by cannabinoid receptor antagonists. For their use for.

Background Obesity is a major public health concern because of the increased prevalence of obesity and the associated health risks. Obesity and overweight are generally defined by the body mass index (BMI), which correlates with total body fat and estimates the relative risk of disease. BMI (kg / m ² ) is calculated by dividing weight (kg) by the square of height (m). The overweight typically, BMI is defined as 25~29.9kg / m ^2, and obesity is typically BMI is defined as 30kg / m ^2. For example, the National Heart, Lung, and Blood Institute (NHLBI) `` Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults '', evidence Report, Washington, DC: See US Department of Health (HHS), NIH booklet 98-4083 (1998).

  Increased obesity is associated with coronary heart disease, stroke, hypertension, type 2 diabetes, dyslipidemia, sleep apnea, osteoarthritis, gallbladder disease, depression, and certain types of cancer (e.g. endometrial cancer, breast cancer) , Prostate cancer, and colon cancer) are of concern because of excessive health risks associated with obesity. In the United States, the negative health consequences of obesity make it the second most preventable cause of death, which has significant economic and social psychological effects on society. See McGinnis M, Foege WH., “Actual Causes of Death in the United States”, JAMA, 270, 2207-12 (1993).

  Obesity is now recognized as a chronic disease that requires treatment to reduce its associated health risks. Weight loss is an important treatment outcome, but one of the main goals of obesity management is to improve cardiovascular and metabolic values to reduce the prevalence and mortality associated with obesity It is. It has been shown that a loss of 5-10% of body weight can substantially improve metabolic values such as blood glucose levels, blood pressure, and lipid concentrations. Thus, it is believed that an intentional decrease in body weight of 5-10% can reduce morbidity and mortality.

Currently, prescription drugs available to manage obesity generally reduce body weight by inducing satiety or reducing dietary fat absorption. Saturation is achieved by increasing the concentration of norepinephrine, serotonin or both synapses. For example, stimulation of serotonin receptor subtypes 1b, 1d, and 2c and 1- and 2-adrenergic receptors reduces food intake by regulating satiety. See Bray GA, “The New Era of Drug Treatment. Pharmacologic Treatment of Obesity: Symposium Overview” Obes Res ., 3 (suppl 4), 415s-7s (1995). Adrenergic drugs (eg, diethylpropyne, benzphetamine, phendimetrazine, mazindol, and phentermine) act by modulating central norepinephrine and dopamine receptors through promoting catecholamine release. Older adrenergic weight loss drugs (eg, amphetamine, methamphetamine, and phenmetrazine) are strongly involved in the dopamine pathway but are no longer recommended because of their abuse risk. Both fenfluramine and dexfenfluramine are serotonergic agents used to regulate appetite, but they are no longer available for use.

More recently, the potential of CB1 cannabinoid receptor antagonist / irreversible agonists as appetite suppressants has been suggested. For example, Arnone, M. et al., “Selective Inhibition of, Sucrose and Ethanol Intake by SR141716, an Antagonist of Central Cannabinoid (CB1) Receptors”, Psychopharmacol , 132, 104-106 (1997); Colombo, G. et al., “Appetite Suppression and Weight Loss after the Cannabinoid, Antagonist SR141716 ”, Life Sci ., 63, PL113-PL117 (1998); Simiand, J. et al.,“ SR141716, a CB1 Cannabinoid Receptor Antagonist, Selectively Reduces Sweet Food Intake in Marmose ”, Behav Pharmacol. , 9,179-181 (1998); and Chaperon, F. et al., “Involvement of Central Cannabinoid (CB1) Receptors in the Establishment of Place Conditioning in Rats”, Psychopharmacology , 135, 324-332 (1998). That. For a review of cannabinoid CB1 and CB2 receptor modulators, see Pertwee, RG, "Cannabinoid Receptors Ligands: Clinical and Neuropharmacological Considerations, Relevant to Future Drug Discovery and Development," Exp. Opin. Invest. Drugs , 9 (7), 1553- See 1571 (2000).

  While research continues, there is still a need for more effective and safe therapeutic treatments to reduce or prevent weight gain.

In addition to obesity, there is an unmet need for treatment of alcoholism. Alcoholism affects approximately 10.9 million men and 4.4 million women in the United States. Approximately 100,000 deaths each year are due to alcoholism or dependence. Health risks associated with alcoholism include impaired motor control and determination, cancer, liver disease, birth defects, heart disease, drug interactions, pancreatitis and interpersonal problems. Research suggests that endogenous cannabinoid tone plays an important role in the management of ethanol intake. The endogenous CB1 receptor antagonist SR-141716A has been shown to interfere with spontaneous ethanol intake in rats and mice. See Arnone, M. et al., “Selective Inhibition of Sucrose and Ethanol Intake by SR141716, an Antagonist of Central Cannabinoid (CB1) Receptors”, Psychopharmacol , 132, 104-106 (1997). For a review, see Hungund, B. L and BS Basavarajappa, “Are Anand amide and Cannabinoid Receptors involved in Ethanol Tolerance? A Review of the Evidence” Alcohol & Alcoholism . 35 (2) 126-133,2000.

  Current treatments for alcoholism or addiction generally suffer from non-compliance or potential hepatotoxicity; as a result, there is a high unmet need for a more effective treatment for alcoholism / dependence.

SUMMARY The present invention is a compound of formula (I) or (II) that acts as a cannabinoid receptor ligand (particularly a CB1 receptor antagonist):

[Where
R ¹ is optionally substituted aryl or optionally substituted heteroaryl (preferably R ¹ is substituted phenyl, more preferably halo (preferably chloro or fluoro), (C ₁ -C ₄ ) ₁ independently selected from the group consisting of alkoxy, (C ₁ -C ₄ ) alkyl, halo-substituted (C ₁ -C ₄ ) alkyl (preferably fluoro-substituted alkyl), and cyano Phenyl substituted with ~ 3 substituents, most preferably R ¹ is 2-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4- Fluorophenyl or 2,4-difluorophenyl). );
R ² is optionally substituted aryl or optionally substituted heteroaryl (preferably R ² is substituted phenyl, more preferably halo (preferably chloro or fluoro), (C ₁ -C ₄ ) ₁ independently selected from the group consisting of alkoxy, (C ₁ -C ₄ ) alkyl, halo-substituted (C ₁ -C ₄ ) alkyl (preferably fluoro-substituted alkyl), and cyano Phenyl substituted with ~ 3 substituents, most preferably R ² is 4-chlorophenyl or 4-fluorophenyl);
R ³ is hydrogen, (C ₁ -C ₄ ) alkyl, halo-substituted (C ₁ -C ₄ ) alkyl, or aryl;
R ⁴ is
(i) a group having formula (IA) or formula (IB):

(Where
R ^4a is hydrogen or (C ₁ -C ₃ ) alkyl;
R ^4b and R ^{4b ′} are each independently hydrogen, cyano, hydroxy, amino, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, Acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)- , (C ₁ -C ₆ ) alkylamino-, ((C ₁ -C ₄ ) alkyl) ₂ amino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkyl Amino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3-6 membered partially or fully A chemical moiety selected from the group consisting of saturated carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents,
Or either R ^4b or R ^{4b ′} together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge;
X is a bond, —CH ₂ CH ₂ — or —C (R ^4c ) (R ^{4c ′} ) —, wherein R ^4c and R ^{4c ′} are each independently hydrogen, cyano, hydroxy, amino, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C _1- C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, di (C ₁ -C ₄ ) alkyl Amino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3- A chemical moiety selected from the group consisting of a 6-membered partially or fully saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein The moiety is optionally substituted with one or more substituents,
Or either R ^4c or R ^{4c ′} together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge;
Y is oxygen, sulfur, -C (O)-, or -C (R ^4d ) (R ^{4d '} )-, where R ^4d and R ^4d' are each independently hydrogen, cyano, hydroxy , Amino, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, ( C ₁ -C ₄₎ alkyl -NH-C (O) -, ((C 1 -C 4) _{alkyl) 2 NC (O) -,} (C 1 -C 6) alkylamino -, di (C ₁ -C ₄₎ alkylamino -, (C ₃ -C ₆₎ cycloalkylamino -, acylamino -, aryl (C ₁ -C ₄₎ alkylamino -, heteroaryl (C ₁ -C ₄₎ alkylamino -, aryl, heteroaryl A chemical moiety selected from the group consisting of a 3-6 membered partially or fully saturated heterocyclic ring, and a 3-6 membered partially or fully saturated carbocyclic ring, Wherein the moiety is optionally substituted with one or more substituents,
Or R ^4d and R ^{4d ′} together are a 3-6 membered partially or fully saturated heterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactam ring. Wherein the heterocyclic ring, the lactone ring and the lactam ring are optionally substituted with one or more substituents, and the lactone ring and the lactam ring are optionally selected from oxygen, nitrogen or sulfur Containing heteroatoms, or
Y is —NR ^{4d ″} —, where R ^{4d ″} is hydrogen or (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₃ ) alkylsulfonyl-, The group consisting of (C ₁ -C ₃ ) alkylaminosulfonyl-, di (C ₁ -C ₃ ) alkylaminosulfonyl-, acyl, (C ₁ -C ₆ ) alkyl-OC (O)-, aryl, and heteroaryl A chemical moiety selected from, wherein the moiety is optionally substituted with one or more substituents;
Z is a bond, —CH ₂ CH ₂ —, or —C (R ^4e ) (R ^{4e ′} ) —, wherein R ^4e and R ^{4e ′} are each independently hydrogen, cyano, hydroxy, amino , H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, di (C ₁ -C ₄ ) alkylamino -, (C ₃ -C ₆₎ cycloalkylamino -, acylamino -, aryl (C ₁ -C ₄₎ alkylamino -, heteroaryl (C ₁ -C ₄₎ alkylamino -, aryl, heteroaryl, 3 A chemical moiety selected from the group consisting of a -6 membered partially or fully saturated heterocyclic ring and a 3-6 membered partially or fully saturated carbocyclic ring, wherein The moiety is optionally substituted with one or more substituents,
Or either R ^4e or R ^{4e ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge; and
R ^4f and R ^{4f ′} are each independently hydrogen, cyano, hydroxy, amino, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, Acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)- , (C ₁ -C ₆ ) alkylamino-, di (C ₁ -C ₄ ) alkylamino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino- Heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3-6 membered partially or fully saturated Or a chemical moiety selected from the group consisting of carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents,
Alternatively, either R ^4f or R ^{4f ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge. );
(ii) a group having the formula (IC):

Wherein R ⁵ and R ⁶ are each independently hydrogen or (C ₁ -C ₄ ) alkyl, and R ⁷ is an optionally substituted (C ₁ -C ₄ ) alkyl-, or An optionally substituted 4-6 membered partially or fully saturated heterocyclic ring containing 1-2 heteroatoms independently selected from oxygen, sulfur, or nitrogen;
Or R ⁵ and R ⁶ or R ⁵ and R ⁷ together are ^1-6 heteroatoms independently selected from 5-6 membered lactones, 4-6 membered lactams, oxygen, sulfur, or nitrogen. Forms a 4-6 membered partially or fully saturated heterocycle containing two, wherein the lactone, the lactam and the heterocycle are optionally substituted with one or more substituents . ;; or
(iii) (C ₁ -C ₈ ) alkyl, aryl (C ₁ -C ₄ ) alkyl, partially or fully saturated (C ₃ -C ₈ ) cycloalkyl, hydroxy (C ₁ -C ₆ ) alkyl , (C ₁ -C ₃ ) alkoxy (C ₁ -C ₆ ) alkyl, heteroaryl (C ₁ -C ₃ ) alkyl, and at least one selected from the group consisting of fully or partially saturated heterocycles A chemical moiety is an amino group attached thereto, wherein the moiety is optionally substituted with one or more substituents. ]
Or a pharmaceutically acceptable salt thereof, a prodrug of the compound or salt, or a solvate or hydrate of the compound, salt or prodrug.

  In another embodiment of the invention, the formula (III) or (IV):

[Where
R ^1a , R ^1b , R ^2a , and R ^2b are each independently halo, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, halo-substituted (C ₁ -C ₄ ) Alkyl or cyano;
n and m are each independently 0, 1 or 2;
R ³ is hydrogen, (C ₁ -C ₄ ) alkyl, halo-substituted (C ₁ -C ₄ ) alkyl, or aryl; and
R ⁴ is a group having (i) formula (IA) or formula (IB):

(Where
R ^4a is hydrogen or (C ₁ -C ₃ ) alkyl;
R ^4b and R ^{4b ′} are each independently hydrogen, cyano, hydroxy, amino, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, Acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)- , (C ₁ -C ₆ ) alkylamino-, ((C ₁ -C ₄ ) alkyl) ₂ amino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkyl Amino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3-6 membered partially or fully A chemical moiety selected from the group consisting of saturated carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents,
Or either R ^4b or R ^{4b ′} together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge;
X is a bond, —CH ₂ CH ₂ — or —C (R ^4c ) (R ^{4c ′} ) —, wherein R ^4c and R ^{4c ′} are each independently hydrogen, cyano, hydroxy, amino, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C _1- C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, di (C ₁ -C ₄ ) alkyl Amino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3- A chemical moiety selected from the group consisting of a 6-membered partially or fully saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein The moiety is optionally substituted with one or more substituents,
Or either R ^4c or R ^{4c ′} together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge;
Y is oxygen, sulfur, -C (O)-, or -C (R ^4d ) (R ^{4d '} )-, where R ^4d and R ^4d' are each independently hydrogen, cyano, hydroxy , Amino, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, ( C ₁ -C ₄₎ alkyl -NH-C (O) -, ((C 1 -C 4) _{alkyl) 2 NC (O) -,} (C 1 -C 6) alkylamino -, di (C ₁ -C ₄₎ alkylamino -, (C ₃ -C ₆₎ cycloalkylamino -, acylamino -, aryl (C ₁ -C ₄₎ alkylamino -, heteroaryl (C ₁ -C ₄₎ alkylamino -, aryl, heteroaryl A chemical moiety selected from the group consisting of a 3-6 membered partially or fully saturated heterocyclic ring, and a 3-6 membered partially or fully saturated carbocyclic ring, Wherein the moiety is optionally substituted with one or more substituents,
Or R ^4d and R ^{4d ′} together are a 3-6 membered partially or fully saturated carbocyclic ring, a 3-6 membered partially or fully saturated heterocyclic ring , A 5-6 membered lactone ring, or a 4-6 membered lactam ring, wherein the carbocyclic ring, the heterocyclic ring, the lactone ring and the lactam ring are optionally substituted by one or more substituents Substituted and the lactone and lactam rings optionally contain a heteroatom selected from oxygen, nitrogen or sulfur, or
Y is —NR ^{4d ″} —, where R ^{4d ″} is hydrogen or (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₃ ) alkylsulfonyl-, The group consisting of (C ₁ -C ₃ ) alkylaminosulfonyl-, di (C ₁ -C ₃ ) alkylaminosulfonyl-, acyl, (C ₁ -C ₆ ) alkyl-OC (O)-, aryl, and heteroaryl A chemical moiety selected from, wherein the moiety is optionally substituted with one or more substituents;
Z is a bond, —CH ₂ CH ₂ —, or —C (R ^4e ) (R ^{4e ′} ) —, wherein R ^4e and R ^{4e ′} are each independently hydrogen, cyano, hydroxy, amino , H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, di (C ₁ -C ₄ ) alkylamino -, (C ₃ -C ₆₎ cycloalkylamino -, acylamino -, aryl (C ₁ -C ₄₎ alkylamino -, heteroaryl (C ₁ -C ₄₎ alkylamino -, aryl, heteroaryl, 3 A chemical moiety selected from the group consisting of a -6 membered partially or fully saturated heterocyclic ring and a 3-6 membered partially or fully saturated carbocyclic ring, wherein The moiety is optionally substituted with one or more substituents,
Or either R ^4e or R ^{4e ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge; and
R ^4f and R ^{4f ′} are each independently hydrogen, cyano, hydroxy, amino, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, Acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)- , (C ₁ -C ₆ ) alkylamino-, di (C ₁ -C ₄ ) alkylamino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino- Heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3-6 membered partially or fully saturated Or a chemical moiety selected from the group consisting of carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents,
Alternatively, either R ^4f or R ^{4f ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge. );
(ii) a group having the formula (IC):

Wherein R ⁵ and R ⁶ are each independently hydrogen or (C ₁ -C ₄ ) alkyl, and R ⁷ is a halo-substituted (C ₁ -C ₄ ) alkyl-, ( C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkyl-, (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkyl-, di (C ₁ -C ₄ ) alkylamino (C _1- C ₄₎ alkyl -, or oxygen, sulfur, or containing 1 to 2 an independently selected heteroatom from nitrogen, 4-6 membered partially or fully saturated heterocyclic ring,
Or R ⁵ and R ⁶ or R ⁵ and R ^{7 taken} together are a 5-6 membered lactone, a 4-6 membered lactam, or a heteroatom independently selected from oxygen, sulfur, or nitrogen. Or a 4-6 membered partially or fully saturated heterocycle containing two, wherein the lactone, the lactam and the heterocycle are optionally substituted with one or more substituents. Yes. );
(iii) (C ₁ -C ₈ ) alkyl, aryl (C ₁ -C ₄ ) alkyl, partially or fully saturated (C ₃ -C ₈ ) cycloalkyl, hydroxy (C ₁ -C ₆ ) alkyl , (C ₁ -C ₃ ) alkoxy (C ₁ -C ₆ ) alkyl, heteroaryl (C ₁ -C ₃ ) alkyl, and at least one selected from the group consisting of fully or partially saturated heterocycles A chemical moiety is an amino group attached thereto, wherein the moiety is optionally substituted with one or more substituents;
(iv) hydroxy, (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylamino, di ((C ₁ -C ₆ ) alkyl) amino (C ₁ -C ₃ ) alkylsulfonyl, (C ₁ -C ₃₎ alkyl sulfamyl, di ((C ₁ -C ₃₎ alkyl) sulfamyl, acyloxy, a partially or fully saturated heterocycle, and a partially or fully saturated carbocyclic A (C ₁ -C ₆ ) alkyl group to which is attached at least one chemical moiety selected from the group consisting of a ring, wherein the chemical moiety is one or more substituents Is optionally substituted by ]
Or a pharmaceutically acceptable salt thereof, a prodrug of the compound or salt, or a solvate or hydrate of the compound, salt or prodrug.

Preferred compounds of the invention are compounds of formula (I), (II), (III) or (IV) (wherein R ⁴ is a group of formula (IA)). Preferably, R ^4b and R ^{4b ′} are each independently hydrogen, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC (O )-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, aryl, heteroaryl, 3-6 membered partially Or a chemical moiety selected from the group consisting of a fully saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein the moiety is optionally one Or substituted with multiple substituents, or either R ^4b or R ^{4b ′} together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge;
X is a bond, —CH ₂ CH ₂ — or —C (R ^4c ) (R ^{4c ′} ) —, where R ^4c is hydrogen, cyano, hydroxy, amino, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C ( O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, ((C ₁ -C ₄ ) alkyl) ₂ amino-, (C _3- C ₆₎ cycloalkylamino -, acylamino -, aryl (C ₁ -C ₄₎ alkylamino -, heteroaryl (C ₁ -C ₄₎ alkylamino -, aryl, heteroaryl, 3-6 membered partially or A chemical moiety selected from the group consisting of fully saturated heterocycles and 3-6 membered partially or fully saturated carbocyclic rings, wherein the moiety is optionally one Or substituted with a plurality of substituents, or R ^4c , together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} , Forming a methylene or ethylene bridge; and R ^{4c ′} is hydrogen, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC (O )-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, aryl, heteroaryl, 3-6 membered partially Or a chemical moiety selected from the group consisting of a fully saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein the moiety is optionally 1 either substituted by number or more substituents, or, R ^{4c 'is,} R ^4e, R ^4e' with, R ^4f or R ^{4f ',} forms a bond, a methylene bridge or an ethylene bridge;
Y is oxygen, sulfur, -C (O)-, or -C (R ^4d ) (R ^{4d '} )-, where R ^4d is hydrogen, cyano, hydroxy, amino, H ₂ NC (O) -, or (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, acyloxy, acyl, (C ₁ -C ₃₎ alkyl -OC (O) -, (C 1 -C 4) alkyl -NH -C (O) -, (( C 1 -C 4) _{alkyl) 2 NC (O) -,} (C 1 -C 6) alkylamino -, ((C ₁ -C ₄₎ alkyl) ₂ amino -, ( C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered moiety A chemical moiety selected from the group consisting of a partially or fully saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein the moiety is optional substituted with one or more substituents, and, R ^{4d 'is} _{hydrogen, H 2 NC (O) -} , or (C ₁ -C ₆₎ alkyl Acyl, (C ₁ -C ₃₎ alkyl -OC (O) -, (C 1 -C 4) alkyl -NH-C (O) -, ((C 1 -C 4) alkyl) ₂ NC (O) - A chemistry selected from the group consisting of aryl, heteroaryl, 3-6 membered partially or fully saturated heterocyclic ring, and 3-6 membered partially or fully saturated carbocyclic ring Wherein the moiety is optionally substituted with one or more substituents, or
Or R ^4d and R ^{4d ′} together are a 3-6 membered partially or fully saturated carbocyclic ring, a 3-6 membered partially or fully saturated heterocyclic ring , A 5-6 membered lactone ring, or a 4-6 membered lactam ring, wherein the carbocyclic ring, heterocyclic ring, lactone ring and lactam ring are optionally substituted by one or more substituents And the lactone ring and the lactam ring optionally contain a heteroatom selected from oxygen, nitrogen or sulfur, or
Y is —NR ^{4d ″} —, where R ^{4d ″} is hydrogen or (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₃ ) alkylsulfonyl-, The group consisting of (C ₁ -C ₃ ) alkylaminosulfonyl-, di (C ₁ -C ₃ ) alkylaminosulfonyl-, acyl, (C ₁ -C ₆ ) alkyl-OC (O)-, aryl, and heteroaryl A more selected chemical moiety, wherein the moiety is optionally substituted with one or more substituents;
Z is a bond, -CH ₂ CH _2- , or -C (R ^4e ) (R ^{4e '} )-, where R ^4e is hydrogen, cyano, hydroxy, amino, H ₂ NC (O)-, Or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, ((C ₁ -C ₄ ) alkyl) ₂ amino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered partially Or a chemical moiety selected from the group consisting of a fully saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein the moiety is optionally one Or substituted with a plurality of substituents, or R ^4e , together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} , Forming a ethylene or ethylene bridge; and R ^{4e ′} is hydrogen, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC (O )-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, aryl, heteroaryl, 3-6 membered partially Or a chemical moiety selected from the group consisting of a fully saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein the moiety is optionally one Or substituted with a plurality of substituents, or R ^{4e ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge;
R ^4f and R ^{4f ′} are each independently hydrogen, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC (O) —, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, aryl, heteroaryl, 3-6 membered partially or completely A chemical moiety selected from the group consisting of a saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein the moiety is optionally one or more Substituted with a substituent or either R ^4f or R ^{4f ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge;
A pharmaceutically acceptable salt thereof, or a prodrug of this compound or this salt, or a solvate or hydrate of this compound, this salt or this prodrug.

Preferably, R ^4b forms a bond, a methylene bridge or an ethylene bridge with hydrogen, optionally substituted (C ₁ -C ₃ ) alkyl, or R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} ; R ^{4b ′} together with hydrogen, optionally substituted (C ₁ -C ₃ ) alkyl, or R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge; R ^4f Together with hydrogen, optionally substituted (C ₁ -C ₃ ) alkyl, or R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} form a bond, a methylene bridge or an ethylene bridge; and R ^4f is Together with hydrogen, optionally substituted (C ₁ -C ₃ ) alkyl, or R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} to form a bond, a methylene bridge or an ethylene bridge, even more preferably R ^4b , R ^{4b ′} , R ^4f or R ^{4f ′} are all hydrogen.

When Y is —NR ^{4d ″} —, R ^{4d ″} is preferably hydrogen or (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₃ ) alkylsulfonyl. -, (C ₁ -C ₃ ) alkylaminosulfonyl-, di (C ₁ -C ₃ ) alkylaminosulfonyl-, acyl, (C ₁ -C ₆ ) alkyl-OC (O)-, aryl, and heteroaryl A chemical moiety selected from the group consisting of optionally substituted with one or more substituents (more preferably, R ^{4d ″} is hydrogen, or (C ₁ -C ₃₎ alkylsulfonyl, (C ₁ -C ₃₎ alkylaminosulfonyl, di (C ₁ -C ₃₎ alkyl aminosulfonyl, acyl, (C ₁ -C ₆₎ alkyl -OC (O) -, and consists heteroaryl Wherein the moiety is optionally substituted with one or more substituents (preferably a (C ₁ -C ₃ ) alkylsulfonate. , (C ₁ -C ₃ ) alkylaminosulfonyl, di (C ₁ -C ₃ ) alkylaminosulfonyl, acyl, and (C ₁ -C ₆ ) alkyl-OC (O)-are 1 to 3 fluorines And heteroaryl consists of chloro, fluoro, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₃ ) alkyl, and fluorine-substituted (C ₁ -C ₃ ) alkyl) Optionally substituted with 1 to 2 substituents independently selected from the group;
X is -C (R ^4c ) (R ^{4c '} )-, wherein R ^4c and R ^4c' are each independently hydrogen, H ₂ NC (O)-, or (C ₁ -C ₆ ) Alkyl, (C ₁ -C ₄ ) alkyl-NH-C (O)-, or ((C ₁ -C ₄ ) alkyl) ₂ NC (O)- Is optionally substituted with one or more substituents,
Or either R ^4c or R ^{4c ′} together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge; and
Z is -C (R ^4e ) (R ^{4e '} )-, wherein R ^4e and R ^4e' are each independently hydrogen, H ₂ NC (O)-, or (C ₁ -C ₆ ) Alkyl, (C ₁ -C ₄ ) alkyl-NH-C (O)-, or ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, where this moiety is optionally one Or substituted with multiple substituents,
Alternatively, either R ^4e or R ^{4e ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge.

When Y is -C (R ^4d ) (R ^{4d '} )-, R ^4d is hydrogen, cyano, hydroxy, amino, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, ( C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, ((C ₁ -C ₄ ) alkyl) ₂ amino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino- , Aryl (C ₁ -C ₄ ) alkylamino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3 A chemical moiety selected from the group consisting of -6-membered partially or fully saturated carbocyclic rings, wherein this moiety is optionally substituted with one or more substituents (preferably R ^4d is amino, (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₄ ) alkylamino, (C ₃ -C ₆ ) cycloalkylamino, acylamino, aryl (C ₁ -C ₄ ) alkylamino-, or heteroaryl (C ₁ -C ₄ ) alkylamino, more preferably R ^4d is amino, (C ₁ -C ₆₎ alkylamino, di (C ₁ -C ₄₎ alkylamino, a (C ₃ -C ₆₎ cycloalkyl amino.), and
R ^{4d '} is hydrogen, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl -NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3 A chemical moiety selected from the group consisting of -6-membered partially or fully saturated carbocyclic rings, wherein this moiety is optionally substituted with one or more substituents (preferably R ^{4d ′} is (C ₁ -C ₆ ) alkyl, H ₂ NC (O)-, (C ₁ -C ₄ ) alkyl-NH—C (O)-, or ((C ₁ -C ₄ ) Alkyl) ₂ NC (O)-, or aryl, more preferably R ^{4d ′} is H ₂ NC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, or ( (C ₁ -C ₄ ) alkyl) ₂ NC (O) —). ),
Or R ^4d and R ^{4d ′} together are a 3-6 membered partially or fully saturated carbocyclic ring, a 3-6 membered partially or fully saturated heterocyclic ring Forming a ring, a 5-6 membered lactone ring, or a 4-6 membered lactam ring, wherein the carbocyclic ring, heterocyclic ring, lactone ring and lactam ring are optionally substituted by one or more Substituted with groups, and the lactone and lactam rings optionally contain additional heteroatoms selected from oxygen, nitrogen or sulfur;
X is a bond or —C (R ^4c ) (R ^{4c ′} ) —, where R ^4c and R ^{4c ′} are each hydrogen; and Z is a bond or —C (R ^4e ) (R ^{4e ′} ) —, where R ^4e and R ^{4e ′} are each hydrogen.

In another preferred compound embodiment, Y is — (C (R ^4d ) (R ^{4d ′} ) —, R ^4b , R ^{4b ′} , R ^4f , and R ^{4f ′} are all hydrogen; R ^4d is , Hydrogen, hydroxy, amino, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₆₎ alkylamino -, and di (C ₁ -C ₄₎ alkylamino - a chemical moiety selected from the group consisting of, wherein the moiety is substituted with one or more substituents optionally ( Preferably, R ^4d consists of hydrogen, hydroxy, amino, or (C ₁ -C ₆ ) alkoxy, acyl, (C ₁ -C ₆ ) alkylamino-, and di (C ₁ -C ₄ ) alkylamino- And R ^{4d ′} is a chemical moiety selected from the group consisting of hydrogen or (C ₁ -C ₆ ) alkyl, aryl and heteroaryl, wherein R ^{4d ′} is a chemical moiety selected from the group And this part Is (preferably substituted with one or more substituents optionally, R ^{4d 'is} a chemical moiety selected from hydrogen, or from (C ₁ -C ₆₎ the group consisting of alkyl and aryl, where the The moiety is optionally substituted with one or more substituents.) In this embodiment, X is preferably —C (R ^4c ) (R ^{4c ′} ) —, where R ^4c and R ^{4c 'are} each independently hydrogen or optionally substituted (C ₁ -C ₆₎ alkyl, or R ^4c or R ^4c' are either, together with R ^4e and R ^{4e ',} bond, methylene Form a bridge or ethylene bridge (preferably R ^4c and R ^{4c ′} are each hydrogen or either R ^4c or R ^{4c ′} form a bond with R ^4e and R ^{4e ′} ; ); And
Z is preferably -C (R ^4e ) (R ^{4e '} )-, where R ^4e and R ^4e' are each independently hydrogen or optionally substituted (C ₁ -C ₆ ) alkyl. Or either R ^4e or R ^{4e ′} together with R ^4c or R ^{4c ′} form a bond, a methylene bridge or an ethylene bridge (preferably R ^4e and R ^{4e ′} are each independently hydrogen Or either R ^4e or R ^{4e ′} together with R ^4c or R ^{4c ′} forms a bond.)

In yet another preferred embodiment of the compound of formula (I), (II), (III) or (IV), Y is —C (R ^4d ) (R ^{4d ′} ) —, and R ^4b , R ^{4b ′} , R ^4f , and R ^{4f ′} are all hydrogen; and R ^4d and R ^{4d ′} together are a 3-6 membered partially or fully saturated carbocyclic ring, 3-6 membered Forming a partially or fully saturated heterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactam ring, wherein the carbocyclic ring, heterocyclic ring, lactone ring and The lactam ring is optionally substituted with one or more substituents, and the lactone ring or lactam ring optionally contains an additional heteroatom selected from oxygen, nitrogen or sulfur (preferably R ^4d and R ^{4 4d '} together form a 5-6 membered lactam ring, wherein the lactam ring is optionally substituted with one or more substituents, and optionally an additional selected from nitrogen or oxygen Hete . Containing atoms) in this embodiment, X is preferably a bond, -CH ₂ CH ₂ - or ^{-C (R 4c) (R 4c} ') - a, where in R ^4c and R ^4c' are each Independently, hydrogen, or optionally substituted (C ₁ -C ₆ ) alkyl, or either R ^4c or R ^{4c ′} is bound together with R ^4e or R ^{4e ′} , a methylene bridge or an ethylene bridge (More preferably, X is a bond or —C (R ^4c ) (R ^{4c ′} ) —, where R ^4c and R ^{4c ′} are each hydrogen);
Z is preferably a bond, —CH ₂ CH ₂ — or —C (R ^4e ) (R ^{4e ′} ) —, where R ^4e and R ^{4e ′} are each independently hydrogen or optionally substituted. (C ₁ -C ₆ ) alkyl, or either R ^4e or R ^{4e ′} together with either R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge (more preferably Z Is a bond or —C (R ^4e ) (R ^{4e ′} ) —, where R ^4e and R ^{4e ′} are each hydrogen.

Another aspect of the present invention is a compound of formula (I), (II), (III) or (IV), wherein R ⁴ is a group of formula (IB), wherein R ^4a is As defined above, R ^4b is hydrogen, cyano, hydroxy, amino, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, ( C ₁ -C ₆₎ alkylamino -, ((C ₁ -C ₄₎ alkyl) ₂ amino -, (C ₃ -C ₆₎ cycloalkylamino -, acylamino -, aryl (C ₁ -C ₄₎ alkylamino - Heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3-6 membered partially or fully saturated A chemical moiety selected from the group consisting of a carbocyclic ring, wherein the moiety is optionally one or more substituents Or it is replaced,
R ^{4b ′} is hydrogen, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC (O) —, (C ₁ -C ₄ ) alkyl -NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3 A chemical moiety selected from the group consisting of -6-membered partially or fully saturated carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents ,
Or R ^4b or R ^{4b ′} together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge;
X is a bond, —CH ₂ CH ₂ — or —C (R ^4c ) (R ^{4c ′} ) —, where R ^4c is hydrogen, cyano, hydroxy, amino, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C ( O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, ((C ₁ -C ₄ ) alkyl) ₂ amino-, (C _3- C ₆₎ cycloalkylamino -, acylamino -, aryl (C ₁ -C ₄₎ alkylamino -, heteroaryl (C ₁ -C ₄₎ alkylamino -, aryl, heteroaryl, 3-6 membered partially or A chemical moiety selected from the group consisting of fully saturated heterocycles and 3-6 membered partially or fully saturated carbocyclic rings, wherein the moiety is optionally one Or R ^4c is ^bonded to R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} , Forming a tylene bridge or an ethylene bridge, and R ^{4c ′} is hydrogen, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC (O) -, (C ₁ -C ₄₎ alkyl -NH-C (O) -, ((C 1 -C 4) alkyl) ₂ NC (O) -, aryl, heteroaryl, 3-6 membered partially or A chemical moiety selected from the group consisting of fully saturated heterocycles and 3-6 membered partially or fully saturated carbocyclic rings, wherein the moiety is optionally one Or substituted with a plurality of substituents, or R ^{4c ′} together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge (preferably X is A bond, -CH ₂ CH ₂ -or -C (R ^4c ) (R ^{4c '} )-, wherein R ^4c and R ^4c' are each independently hydrogen or (C ₁ -C ₆ ) alkyl. is there.);
Y is oxygen, sulfur, -C (O)-, or -C (R ^4d ) (R ^{4d '} )-, where R ^4d is hydrogen, cyano, hydroxy, amino, H ₂ NC (O) -, or (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, acyloxy, acyl, (C ₁ -C ₃₎ alkyl -OC (O) -, (C 1 -C 4) alkyl -NH -C (O) -, (( C 1 -C 4) _{alkyl) 2 NC (O) -,} (C 1 -C 6) alkylamino -, ((C ₁ -C ₄₎ alkyl) ₂ amino -, ( C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered moiety A chemical moiety selected from the group consisting of a partially or fully saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein the moiety is optional substituted with one or more substituents, and, R ^{4d 'is} _{hydrogen, H 2 NC (O) -} , or (C ₁ -C ₆₎ alkyl Acyl, (C ₁ -C ₃₎ alkyl -OC (O) -, (C 1 -C 4) alkyl -NH-C (O) -, ((C 1 -C 4) alkyl) ₂ NC (O) - A chemistry selected from the group consisting of aryl, heteroaryl, 3-6 membered partially or fully saturated heterocyclic ring, and 3-6 membered partially or fully saturated carbocyclic ring Wherein the moiety is optionally substituted with one or more substituents, or R ^4d and R ^{4d ′} together are 3-6 membered partially or fully A saturated carbocyclic ring, a 3-6 membered partially or fully saturated heterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactam ring, wherein The carbocyclic ring, heterocyclic ring, lactone ring and lactam ring are optionally substituted with one or more substituents, and the lactone ring and lactam ring are optionally selected from oxygen, nitrogen or sulfur Contains heteroatoms Or
Y is —NR ^{4d ″} —, where R ^{4d ″} is hydrogen or (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₃ ) alkylsulfonyl-, The group consisting of (C ₁ -C ₃ ) alkylaminosulfonyl-, di (C ₁ -C ₃ ) alkylaminosulfonyl-, acyl, (C ₁ -C ₆ ) alkyl-OC (O)-, aryl, and heteroaryl A chemical moiety, wherein the moiety is optionally substituted with one or more substituents (preferably Y is —NR ^{4d ″} —, where R ^{4d ″} is Hydrogen or (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₃ ) alkylsulfonyl-, (C ₁ -C ₃ ) alkylaminosulfonyl-, di (C _1- A chemical moiety selected from the group consisting of C ₃ ) alkylaminosulfonyl-, acyl, (C ₁ -C ₆ ) alkyl-OC (O)-, aryl, and heteroaryl, wherein the moiety is optional 1 Substituted with one or more substituents);
Z is a bond, -CH ₂ CH _2- , or -C (R ^4e ) (R ^{4e '} )-, where R ^4e is hydrogen, cyano, hydroxy, amino, H ₂ NC (O)-, Or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, ((C ₁ -C ₄ ) alkyl) ₂ amino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered partially Or a chemical moiety selected from the group consisting of a fully saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein the moiety is optionally 1 Substituted with one or more substituents, or R ^4e together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} , Methylene bridge or ethylene bridge, and R ^{4e ′} is hydrogen, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC (O )-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, aryl, heteroaryl, 3-6 membered partially Or a chemical moiety selected from the group consisting of a fully saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein the moiety is optionally 1 Substituted with one or more substituents, or R ^{4e ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge (preferably Z is A bond, —CH ₂ CH ₂ — or —C (R ^4c ) (R ^{4c ′} ) —, wherein R ^4c and R ^{4c ′} are each independently hydrogen or (C ₁ -C ₆ ) alkyl. );
R ^4f is hydrogen, cyano, hydroxy, amino, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) Alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkyl Amino-, ((C ₁ -C ₄ ) alkyl) ₂ amino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino-, heteroaryl (C _1- C ₄ ) consisting of alkylamino-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3-6 membered partially or fully saturated carbocyclic ring A chemical moiety selected from the group, wherein the moiety is optionally substituted with one or more substituents; and
R ^{4f ′} is hydrogen, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC (O) —, (C ₁ -C ₄ ) alkyl -NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3 A chemical moiety selected from the group consisting of -6 membered partially or fully saturated carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents ;
Or R ^4f or R ^{4f ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge;
A pharmaceutically acceptable salt thereof, a prodrug of this compound or salt, or a solvate or hydrate of this compound, salt or prodrug.

Yet another embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) wherein R ⁴ has the formula (IC) wherein R ⁵ and R ⁶ are each independently Hydrogen or (C ₁ -C ₄ ) alkyl, and R ⁷ is (C ₁ -C ₄ ) alkyl-, halo-substituted (C ₁ -C ₄ ) alkyl-, (C ₁ -C ₄₎ alkoxy (C ₁ -C ₄₎ alkyl -, (C ₁ -C ₄₎ alkylamino (C ₁ -C ₄₎ alkyl -, di (C ₁ -C ₄₎ alkylamino (C ₁ -C ₄₎ alkyl -Or a substituted 4-6 membered partially or fully saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from oxygen, sulfur or nitrogen, or , R ⁵ and R ⁶ or R ⁵ and R ^{7 taken} together are ^1-6 heteroatoms independently selected from 5-6 membered lactone, 4-6 membered lactam, or oxygen, sulfur, or nitrogen. Form a 4-6 membered partially or fully saturated heterocycle containing two, wherein Lactones, lactams and heterocycles are optionally substituted with one or more substituents.); Pharmaceutically acceptable salts thereof, compounds or prodrugs thereof, or compounds, salts or prodrugs thereof The solvate or hydrate. Preferably, R ⁵ and R ⁶ are each independently hydrogen or (C ₁ -C ₄ ) alkyl, and R ⁷ is (C ₁ -C ₄ ) alkyl.

Preferred compounds of formula (I) or (III) include:
1- [3- (4-Chloro-phenyl) -2- (2-chloro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-cyclohexylamino-piperidine-4-carboxylic acid Acid amides;
4-Benzyl-1- [3- (4-chloro-phenyl) -2- (2-chloro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -piperidin-4-ol;
1- [3- (4-Chloro-phenyl) -2- (2-chloro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-isopropylamino-piperidine-4-carvone Acid amides;
1- [3- (4-Chloro-phenyl) -2- (2-chloro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-ethylamino-piperidine-4-carboxylic acid Acid amides;
1- [3- (4-Chloro-phenyl) -2- (2-chloro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-propylamino-piperidine-4-carboxylic acid Acid amides;
1- [2- (2-Chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-isopropylamino-piperidine-4-carvone Acid amides;
1- [2- (2-Chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-propylamino-piperidine-4-carboxylic acid Acid amides;
1- [2- (2-Chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-ethylamino-piperidine-4-carboxylic acid Acid amides;
1- [2- (2-Chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-cyclohexylamino-piperidine-4-carboxylic acid Acid amides;
1- [2- (2-Chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-pyrrolidin-1-yl-piperidine- 4-carboxylic acid amide;
1- [2- (2-Chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-methylamino-piperidine-4-carvone Acid amides;
8- [2- (2-Chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -1-isopropyl-1,3,8- Triaza-spiro [4.5] decan-4-one;
8- [3- (4-Chloro-phenyl) -2- (2-chloro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -1-isopropyl-1,3,8- Triaza-spiro [4.5] decan-4-one;
2- (2-Chloro-phenyl) -7- (2,5-diaza-bicyclo [2,2,1] hept-2-yl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3, 4-d] pyridazine;
1- [2- (2-chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-ethyl-piperidin-4-ol;
1- [2- (2-chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-phenyl-piperidin-4-ol;
1- {1- [2- (2-Chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-phenyl-piperidine-4 -Il} -Ethanon;
1- [3- (4-chloro-phenyl) -2- (2-chloro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-phenyl-piperidin-4-ol;
1- [2- (2-chloro-phenyl) -3-phenyl-2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-phenyl-piperidin-4-ol;
1- [2- (2-chloro-phenyl) -3-p-tolyl-2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-phenyl-piperidin-4-ol;
1- {1- [3- (4-Chloro-phenyl) -2- (2-chloro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-phenyl-piperidine-4 -Il} -Ethanon;
1- [3- (4-Chloro-phenyl) -2- (2-chloro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -3-ethylamino-azetidine-3-carvone An acid amide; and
1- [2- (2-Chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -3-ethylamino-azetidine-3-carvone Acid amides;
A pharmaceutically acceptable salt thereof, or a hydrate or solvate of this compound or salt.

More preferred compounds of formula (I) or (III) include:
1- [2- (2-Chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-isopropylamino-piperidine-4-carvone Acid amides;
1- [3- (4-Chloro-phenyl) -2- (2-chloro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-ethylamino-piperidine-4-carboxylic acid Acid amides;
1- [3- (4-Chloro-phenyl) -2- (2-chloro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-propylamino-piperidine-4-carboxylic acid Acid amides;
1- [3- (4-Chloro-phenyl) -2- (2-chloro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -3-ethylamino-azetidine-3-carvone Acid amides;
1- [2- (2-Chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -3-ethylamino-azetidine-3-carvone Acid amides;
1- [2- (2-chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-phenyl-piperidin-4-ol;
1- {1- [2- (2-Chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-phenyl-piperidine-4 -Il} -Ethanon;
1- [3- (4-chloro-phenyl) -2- (2-chloro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-phenyl-piperidin-4-ol; as well as
1- {1- [3- (4-Chloro-phenyl) -2- (2-chloro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-phenyl-piperidine-4 -Il} -Ethanon:
A pharmaceutically acceptable salt thereof, or a hydrate or solvate of this compound or salt.

Preferred compounds of formula (II) or (IV) include:
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-isopropylamino-piperidine-4-carboxylic acid Acid amides;
1- [1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-isopropylamino-piperidine-4 -Carboxylic acid amides;
1- [1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-ethylamino-piperidine-4 -Carboxylic acid amides;
1- [1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-methylamino-piperidine-4 -Carboxylic acid amides;
1- [1- (4-Chloro-phenyl) -2- (2-fluoro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-methylamino-piperidine-4-carboxylic acid Acid amides;
1- [1- (4-Chloro-phenyl) -2- (2-fluoro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-ethylamino-piperidine-4-carboxylic acid Acid amides;
1- [1- (4-Chloro-phenyl) -2- (2-fluoro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-isopropylamino-piperidine-4-carboxylic acid Acid amides;
1- [1- (4-Chloro-phenyl) -2- (2-fluoro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-isopropylamino-azetidine-3-carbon Acid amides;
1- [1- (4-Chloro-phenyl) -2- (2-fluoro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-ethylamino-azetidine-3-carboxyl Acid amides;
1- [1- (4-Chloro-phenyl) -2- (2-fluoro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-methylamino-azetidine-3-carboxyl Acid amides;
1- [1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-isopropylamino-azetidine-3 -Carboxylic acid amides;
1- [1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-ethylamino-azetidine-3 -Carboxylic acid amides;
1- (1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl) -3-methylamino-azetidine-3 -Carboxylic acid amides;
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -7-methyl-1H-imidazo [4,5-d] pyridazin-4-yl] -3-isopropylamino-azetidine -3-carboxylic acid amide;
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -7-ethyl-1H-imidazo [4,5-d] pyridazin-4-yl] -3-isopropylamino-azetidine -3-carboxylic acid amide;
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-methylamino-pyrrolidine-3-carvone Acid amides;
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-ethylamino-pyrrolidine-3-carvone Acid amides;
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-isopropylamino-pyrrolidine-3-carvone Acid amides;
2- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -5-methyl-2,5,7- Triaza-spiro [3,4] octane-8-one;
2- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -5-isopropyl-2,5,7- Triaza-spiro [3,4] octane-8-one;
2- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -5-isopropyl-7-methyl-2, 5,7-triaza-spiro [3,4] octane-8-one;
2- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -7-methyl-1H-imidazo [4,5-d] pyridazin-4-yl] -5-isopropyl-7- Methyl-2,5,7-triaza-spiro [3,4] octane-8-one;
2- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -7-methyl-1H-imidazo [4,5-d] pyridazin-4-yl] -5-isopropyl-2, 5,7-triaza-spiro [3,4] octane-8-one; and
8- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -1-isopropyl-1,3,8- Triaza-spiro [4,5] decan-4-one:
A pharmaceutically acceptable salt thereof, or a hydrate or solvate of this compound or salt.

More preferred compounds of formula (II) or (IV) include:
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-isopropylamino-azetidine-3-carvone Acid amides;
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-ethylamino-azetidine-3-carvone Acid amides;
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-methylamino-azetidine-3-carboxyl Acid amides;
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-methylamino-piperidine-4-carvone Acid amides;
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-ethylamino-piperidine-4-carboxylic acid Acid amides;
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-isopropylamino-piperidine-4-carboxylic acid An acid amide; and
8- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -1-isopropyl-1,3,8- Triaza-spiro [4,5] decan-4-one:
A pharmaceutically acceptable salt thereof, or a hydrate or solvate of this compound or salt.

  Some of the compounds described herein can contain one or more chiral centers; as a result, one of ordinary skill in the art will recognize all stereoisomers of the compounds illustrated and discussed (e.g., It will be understood that enantiomers and diastereomers) are within the scope of the present invention. In addition, tautomers of this compound are also within the scope of the invention. Those skilled in the art will recognize that chemical moieties such as α-aminoethers or α-chloroamines are too unstable to separate; therefore, such moieties do not form part of the present invention. I will.

  In another aspect of the invention, there is provided a pharmaceutical composition comprising (1) a compound of the invention; and (2) a pharmaceutically acceptable excipient, diluent or carrier. Preferably, the composition contains a therapeutically effective amount of a compound of the invention. The composition may contain at least one additional pharmaceutical agent (described herein). Preferred substances include nicotinic receptor partial agonists, opioid antagonists (e.g., naltrexone and nalmefene), dopamine agonists (e.g., apomorphine), attention deficit activity disorder (ADHD) therapeutics (e.g., Ritalin (TM), Strattera (TM)). , Concerta ™ and Adderall ™), and anti-obesity drugs (described below).

  In yet another aspect of the present invention, a method of treating a disease, condition or disorder modulated by a cannabinoid receptor (particularly CB1 receptor) antagonist in an animal is provided by a compound of the present invention (or pharmaceutical composition thereof). Administering a therapeutically effective amount to an animal in need of such treatment.

  Diseases, symptoms and / or disorders modulated by cannabinoid receptor antagonists include eating disorders (e.g., overeating, anorexia, and bulimia), weight loss or management (e.g., reduced calorie or food intake, and / or Or appetite suppression), obesity, depression, atypical depression, bipolar disorder, psychosis, schizophrenia, behavioral acuity, reward-related behavioral inhibition (e.g. avoidance of conditioned places, e.g. cocaine- and morphine-induced Suppression of conditioned place preference), substance abuse, dependence disorders, urges, alcohol addiction (e.g., alcohol abuse, addiction and / or dependence to prevent withdrawal symptoms, reduced cravings, and recurrence of alcohol consumption) Treatment), tobacco abuse (e.g., treatment of smoking smoking, smoking cessation and / or dependence to prevent smoking craving and prevention of recurrence), dementia (memory loss, Alzheimer's) -Disease, age-related dementia, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild neurocognitive impairment), male sexual dysfunction (e.g., erectile dysfunction), convulsive disorder, Includes epilepsy, inflammation, gastrointestinal disorders (eg, gastrointestinal motility or forward-promoting dysfunction), attention deficit disorder (ADD / ADHD), Parkinson's disease, and type II diabetes. In preferred embodiments, the method is used to treat weight loss, obesity, bulimia, ADD / ADHD, Parkinson's disease, dementia, alcoholism, and / or tobacco abuse.

The compounds of the present invention can be administered in combination with other pharmaceutical agents. Preferred pharmaceuticals include nicotinic receptor partial agonists, opioid antagonists (e.g., naltrexone (including naltrexone depots, antabuse and nalmefene), dopamine agonists (e.g., apomorphine), ADD / ADHD drugs (e.g., methylphenic acid hydrochloride). Gin (e.g. RitalinTM and ConcertaTM), atomoxetine (e.g. StratteraTM), and amphetamine (e.g. AdderallTM) and anti-obesity drugs, e.g. apo-B / MTP inhibitors, 11β-hydroxysteroid dehydrogenase-1 (11β-HSD type 1) inhibitor, peptide YY _3-36 or analogs thereof, MCR-4 agonist, CCK-A agonist, monoamine reuptake inhibitor, sympathomimetic agent, β ₃ Adrenergic receptor agonist, dopamine receptor agonist, melanocyte-stimulating hormone receptor analog, 5-HT2c receptor agonist Nist, melanin-concentrating hormone receptor antagonist, leptin, leptin analog, leptin receptor agonist, galanin receptor antagonist, lipase inhibitor, bombesin receptor agonist, neuropeptide-Y receptor antagonist (e.g., NPY-5 receptor antagonist (E.g., as described herein below), thyroid mimetics, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor antagonists, orexin receptor antagonists, glucagon-like peptide-1 receptor agonists, hair Ciliary neurotrophic factor, human agouti-related protein antagonist, ghrelin receptor antagonist, histamine 3 receptor antagonist or inverse agonist, and neuromedin U receptor Including gonists.

  Combination therapy comprises a single pharmaceutical composition containing (a) a compound of the invention, at least one additional pharmaceutical agent described herein, and a pharmaceutically acceptable excipient, diluent, or carrier. Or (b) (i) a first composition comprising a compound of the invention and a pharmaceutically acceptable excipient, diluent, or carrier, and (ii) at least as described herein. It can be administered as two separate pharmaceutical compositions, one additional pharmaceutical agent and a second composition comprising a pharmaceutically acceptable excipient, diluent, or carrier. The pharmaceutical compositions can be administered simultaneously or sequentially and in any order.

  In yet another aspect of the invention, a pharmaceutical kit for use by a consumer to treat a disease, condition or disorder modulated by an animal cannabinoid receptor antagonist is provided. The kit comprises a) a suitable dosage form containing a compound of the invention; and b) a dosage form for treating a disease, condition or disorder modulated by an cannabinoid receptor (particularly CB1 receptor) antagonist. Includes instructions describing how to use.

  In yet another embodiment of the invention, the pharmaceutical kit comprises a first dosage form comprising a) (i) a compound of the invention, and (ii) a pharmaceutically acceptable carrier, excipient or diluent; b) (i) a second dosage form comprising an additional agent as described herein; and (ii) a pharmaceutically acceptable carrier, excipient or diluent; and c) a pharmaceutical kit comprising a container. is there.

Definitions As used herein, the term “alkyl” refers to a hydrocarbon radical of the general formula C _n H _{2n + 1} . The alkane radical may be linear or branched. For example, the term “(C ₁ -C ₆ ) alkyl” means a monovalent straight or branched aliphatic group containing 1 to 6 carbon atoms (eg, methyl, ethyl, n- Propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, hexyl, 2 -Methylpentyl, etc.). Similarly, the alkyl portion (ie, alkyl portion) of alkoxy, acyl (eg, alkanoyl), alkylamino, dialkylamino, and alkylthio groups has the same meaning as previously defined. When indicated as “optionally substituted”, the alkane radical or alkyl moiety is independently substituted or selected independently from the group consisting of substituents listed in the definition of “substituted” below, It may be substituted by one or more substituents (generally 1-3 substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl). “Halo-substituted alkyl” means an alkyl group substituted with one or more halogen atoms (eg, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, etc.). Where the alkane radical or alkyl moiety is substituted, this is preferably 1-3 fluoro substituents, or (C ₁ -C ₃ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₂ -C ₃₎ alkenyl, aryl, heteroaryl, 3-～6- membered heterocycle, chloro, cyano, hydroxy, (C ₁ -C ₃₎ alkoxy, aryloxy, amino, (C ₁ -C ₆₎ alkylamino, di -(C ₁ -C ₄ ) alkylamino, aminocarboxylate (i.e. (C ₁ -C ₃ ) alkyl-OC (O) -NH-), hydroxy (C ₂ -C ₃ ) alkylamino, or keto (oxy ), And preferably 1 to 3 fluoro groups, or (C ₁ -C ₃ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₆ ) aryl, 6-membered - heteroaryl, 3-～6- membered heterocycle, (C ₁ -C ₃₎ alkoxy, (C ₁ -C ₄₎ alkylamino or di - (C ₁ -C ₂₎ It is substituted with one substituent selected from alkylamino.

The term "partially or fully saturated carbocyclic ring" (also referred to as "partially or fully saturated cycloalkyl") is either partially or fully hydrogenated. Means a non-aromatic ring which can be present as a monocyclic, bicyclic or spiral ring. Unless otherwise specified, carbocyclic rings are generally 3- to 8-membered rings. For example, a partially or fully saturated carbocyclic ring (or cycloalkyl) is cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl. , Norbornyl (bicyclo [2.2.1] heptyl), norbornenyl, bicyclo [2.2.2] octyl and the like. When referred to as “optionally substituted”, a partially saturated or fully saturated cycloalkyl group is unsubstituted or substituted below in the definition of “substituted” It may be substituted with one or more substituents (typically 1 to 3 substituents) selected independently from the group of groups. Substituted carbocyclic rings also include groups where the carbocyclic ring is fused to a phenyl ring (eg, indanyl). A carbocyclic group may be attached to a chemical entity or moiety by one of the carbon atoms in the carbocyclic ring system. When substituted, the carbocyclic group is preferably (C ₁ -C ₃₎ alkyl, (C ₂ -C ₃₎ alkenyl, (C ₁ -C ₆₎ alkyl indenyl, aryl, heteroaryl, 3-~ 6-membered heterocycle, chloro, fluoro, cyano, hydroxy, (C ₁ -C ₃ ) alkoxy, aryloxy, amino, (C ₁ -C ₆ ) alkylamino, di- (C ₁ -C ₄ ) alkylamino , amino carboxylate (i.e., (C ₁ -C ₃₎ alkyl -0-C (O) -NH-) independently from the group consisting of hydroxy (C ₂ -C ₃₎ alkyl amino, or keto (oxy) Substituted with 1 or 2 selected substituents, more preferably (C ₁ -C ₂ ) alkyl, 3- to 6-membered heterocycle, fluoro, (C ₁ -C ₃ ) alkoxy, (C ₁ Substituted with one or two substituents independently selected from -C ₄ ) alkylamino or di- (C ₁ -C ₂ ) alkylamino. Similarly, the cycloalkyl portion of the group (eg, cycloalkylalkyl, cycloalkylamino, etc.) is as defined above.

The term “partially saturated or fully saturated heterocyclic ring” (also meaning “partially saturated or fully saturated heterocycle”) A non-aromatic ring that is hydrogenated in either and can exist as a monocyclic, bicyclic or helical ring. Unless otherwise specified, heterocyclic rings generally contain 3- to 6-membered containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, or nitrogen. It is a ring. Partially saturated or fully saturated heterocyclic rings are epoxy, aziridinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, pyrrolidinyl, N-methylpyrrolidinyl, imidazolidinyl, imidazolinyl, Includes groups such as piperidinyl, piperazinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl, oxazinyl, morpholino, thiomorpholino, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide. When described as “optionally substituted”, a partially saturated or fully saturated heterocyclic group is unsubstituted or listed below with the definition of “substituted” It may be substituted with one or more substituents (typically 1 to 3 substituents) independently selected from the group of substituents. Substituted heterocyclic rings include groups in which the heterocyclic ring is fused to an aryl or heteroaryl ring (e.g., 2,3-dihydrobenzofuranyl, 2,3-dihydroindolyl, 1,2,3-dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl). When substituted, heterocyclic group preferably (C ₁ -C ₃₎ alkyl, (C ₃ -C ₆₎ cycloalkyl, (C ₂ -C ₄₎ alkenyl, aryl, heteroaryl, 3-to 6 - membered heterocycle, chloro, fluoro, cyano, hydroxy, (C ₁ -C ₃₎ alkoxy, aryloxy, amino, (C ₁ -C ₆₎ alkylamino, di - (C ₁ -C ₃₎ alkylamino, amino carboxylate (i.e., (C ₁ -C ₃₎ alkyl -OC (O) -NH-), or substituted with keto (oxy), and more preferably (C ₁ -C ₃₎ alkyl, (C ₃ -C is substituted heteroaryl, 3-～6- membered heterocycle, or one or two substituents independently selected from fluoro - ₆₎ cycloalkyl, (C ₆₎ aryl, 6-membered. The heterocyclic group may be attached to the chemical entity or moiety by one ring atom within the heterocyclic ring system. Similarly, the heterocyclic portion of the group (eg, heterocycle-substituted alkyl, heterocycle carbonyl, etc.) is as defined above.

The term “aryl” or “aromatic carbocyclic ring” means an aromatic moiety having a single ring system (eg, phenyl) or fused ring systems (eg, naphthalene, anthracene, phenanthrene, etc.). A typical aryl group is a 6- to 10-membered aromatic carbocyclic ring (s). When described as “optionally substituted”, an aryl group is one that is unsubstituted or independently selected from the group of substituents listed below with the definition of “substituted” Alternatively, it may be substituted with a plurality of substituents (preferably not more than 3 substituents). Substituted aryl groups include a chain of aromatic moieties (eg, biphenyl, terphenyl, phenylnaphthalyl, etc.). When substituted, the aromatic moiety is preferably (C ₁ -C ₄ ) alkyl, (C ₂ -C ₃ ) alkenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, bromo, chloro, fluoro, iodo, cyano, hydroxy, (C ₁ -C ₄₎ alkoxy, aryloxy, amino, (C ₁ -C ₆₎ alkylamino, di - (C ₁ -C ₃₎ alkylamino, or amino carboxylate (i.e. , (C ₁ -C ₃ ) alkyl-OC (O) -NH-) independently substituted with 1 or 2 substituents, more preferably (C ₁ -C ₄ ) alkyl, chloro Substituted with 1 or 2 substituents independently selected from, fluoro, cyano, hydroxy, or (C ₁ -C ₄ ) alkoxy. The aryl group may be attached to the chemical entity or moiety by one of the carbon atoms in the aromatic ring system. Similarly, aryl moieties (ie aromatic moieties) such as aroyl, aroyloxy (ie (aryl) -C (O) —O—), aryl-substituted alkyl, etc. are as defined above.

The term “heteroaryl” or “heteroaromatic ring” refers to an aromatic moiety that includes at least one heteroatom (eg, oxygen, sulfur, nitrogen, or combinations thereof) within a 5- to 10-membered aromatic ring system. Meaning (e.g., pyrrolyl, pyridyl, pyrazolyl, indolyl, indazolyl, thienyl, furanyl, benzofuranyl, oxazolyl, imidazolyl, tetrazolyl, triazinyl, pyrimidyl, pyrazinyl, thiazolyl, purinyl, benzimidazolyl, quinolinyl, isoquinolinyl, benzothiophenyl, Benzoxazolyl). The heteroaromatic moiety can consist of a single ring system or a fused ring system. Typical heteroaryl monocycles are 5- to 6-membered rings containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and typical heteroaryl fused ring systems are: 9- to 10-membered ring systems containing 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen. When noted as “optionally substituted”, a heteroaryl group is unsubstituted or independently selected from the group of substituents listed below with the definition of “substituted”. It may be substituted with one or more substituents (preferably no more than 3 substituents). When substituted, the heteroaromatic moieties are preferably, (C ₁ -C ₄₎ alkyl, (C ₂ -C ₃₎ alkenyl, aryl, heteroaryl, 3-～6- membered heterocycle, bromo, chloro , fluoro, iodo, cyano, hydroxy, (C ₁ -C ₄₎ alkoxy, aryloxy, amino, (C ₁ -C ₆₎ alkylamino, di - (C ₁ -C ₃₎ alkylamino, or amino carboxylate ( That is, substituted with one or two substituents independently selected from (C ₁ -C ₃ ) alkyl-OC (O) -NH-), more preferably (C ₁ -C ₄ ) alkyl, chloro 1 or 2 substitutions independently selected from fluoro, cyano, hydroxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkylamino or di- (C ₁ -C ₂ ) alkylamino Substituted with a group. A heteroaryl group may be attached to the chemical entity or moiety by any one of the atoms within the aromatic ring system (e.g., imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazole) -5-yl, pyridi-2-yl, pyridi-3-yl, pyridi-4-yl, pyridi-5-yl, or pyridi-6-yl). Similarly, a heteroaryl moiety (ie, heteroaromatic moiety) such as heteroaroyl (ie, (heteroaryl) -C (O) -O-), or heteroaryl-substituted alkyl is as defined above.

The term “acyl” refers to alkyl, partially saturated or fully saturated cycloalkyl, partially saturated or fully saturated heterocycle, aryl, and heteroaryl substituted carbonyl groups. To do. For example, acyl, (C ₁ -C ₆₎ alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, valeryl, caproyl, t- butyl acetyl, etc.), (C ₃ -C ₆₎ cycloalkylcarbonyl (e.g., cyclopropyl Carbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (for example, pyrrolidinylcarbonyl, pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperidinylcarbonyl, tetrahydrofuranylcarbonyl, etc.) ), Aroyl (e.g. benzoyl) and heteroaroyl (e.g. thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl, furanyl-3-carbonyl, 1H-pyroyl-2-carbonyl, 1H-pyroyl-3- Carbonyl, benzo [b] thiophenyl-2-ca Boniru, etc.) include groups such as. In addition, the alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl portions of the acyl group may be any one of the groups described in the preceding definitions. When described as “optionally substituted”, an acyl group is one that is unsubstituted or independently selected from the group of substituents listed below with the definition of “substituted” Or optionally substituted with multiple substituents (typically 1 to 3 substituents), or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl moieties of the acyl group are each preferred and It may be substituted as described above in the list of more preferred substituents.

The term “substituted” specifically contemplates and allows for one or more substituents that are common in the art. However, it will be appreciated by those skilled in the art that, in general, substituents must be selected so as not to adversely affect the pharmacological characteristics of the compound or to adversely interfere with pharmaceutical use. Suitable substituents for any of the groups defined above are (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) Alkyl indenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, halo (eg, chloro, bromo, iodo and fluoro), cyano, hydroxy, (C ₁ -C ₆ ) alkoxy, aryloxy, sulfhydryl (Mercapto), (C ₁ -C ₆ ) alkylthio, arylthio, amino, mono- or di- (C ₁ -C ₆ ) alkylamino, quaternary ammonium salt, amino (C ₁ -C ₆ ) alkoxy, aminocarboxylate (i.e., (C ₁ -C ₆₎ alkyl -OC (O) -NH-), hydroxy (C ₂ -C ₆₎ alkylamino, amino (C ₁ -C ₆₎ alkylthio, cyanoamino, nitro, (C ₁ - C ₆ ) carbamyl, keto (oxy), acyl, (C ₁ -C ₆ ) alkyl-CO _2- , glycolyl, glycyl, hydra Includes dino, guanyl, sulfamyl, sulfonyl, sulfinyl, thio (C ₁ -C ₆ ) alkyl-C (O) —, thio (C ₁ -C ₆ ) alkyl-CO ₂ —, and combinations thereof. For substituted combinations such as “substituted aryl (C ₁ -C ₆ ) alkyl”, either the aryl or alkyl group is substituted, or both the aryl and alkyl groups are one or more (Typically 1 to 3 substituents except for perhalogen substitutions). An aryl or heteroaryl substituted carbocyclic or heterocyclic group may be a fused ring (eg, indanyl, dihydrobenzofuranyl, dihydroindolyl, etc.).

  The term `` solvate '' refers to a molecular complex of a compound of formula (I), (II), (III) or (IV) with one or more solvent molecules (as their prodrugs and pharmaceuticals). Including acceptable salts). Such solvent molecules are those commonly used in the pharmaceutical arts and are known to be innocuous to the recipient, such as water, ethanol, and the like. The term “hydrate” means a complex in which the solvent molecule is water.

The term “protecting group” or “Pg” means a substituent that is commonly used to block or protect a particular functionality while reacting with other functional groups of the compound. For example, an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality of the compound. Suitable amino-protecting groups are acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, “hydroxy-protecting group” means a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. “Carboxy-protecting group” means a substituent of a carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups are --CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitro Phenylphenyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see TW Greene's "Protective Groups in Organic Synthesis", John Wiley, & Sons, New York, 1991.

  The phrase “therapeutically effective amount” refers to (i) treating or preventing a particular disease, symptom or disorder, (ii) attenuating, ameliorating or eliminating one or more symptoms of a particular disease, symptom or disorder. Or (iii) means an amount of a compound of the invention that prevents or delays the onset of one or more symptoms of a particular disease, symptom or disorder described herein.

  The term “animal” refers to humans (male or female), pet animals (eg, dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar animal species. “Edible animals” means food-source animals such as cows, pigs, sheep, and poultry.

  The phrase “pharmaceutically acceptable” means that the substance or composition is chemically and / or toxicologically compatible with the other ingredients that the formulation comprises and / or the mammal treated therewith. .

  The terms “treating”, “treating” or “treatment” mean both protective, ie prophylactic and palliative treatment.

  The term “modulated by cannabinoid receptors” or “modulation by cannabinoid receptors” means activation or deactivation of cannabinoid receptors. For example, the ligand can act as an agonist, partial agonist, inverse agonist, antagonist, or partial antagonist.

  The term “antagonist” as used herein includes inverse agonists in addition to full and partial antagonists.

  The term “CB-1 receptor” means a G-protein bound to a type 1 cannabinoid receptor.

  The term “a compound of the invention” (unless otherwise specified) means a compound of formula (I), formula (II), formula (III), or formula (IV) (formula II-A, IV -A, II-B and IV-B), their prodrugs, pharmaceutically acceptable salts of this compound, and / or prodrug, and water of this compound, salt, and / or prodrug In addition to solvates or solvates, all stereoisomers (including diastereomers and enantiomers), tautomers and radiolabeled compounds are included.

DETAILED DESCRIPTION The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and / or disorders modulated by cannabinoid receptor antagonists.

The compounds of the present invention can be synthesized by synthetic routes involving processes similar to those well known in the chemical arts, particularly in light of the description contained herein. Starting materials are generally available from commercial suppliers such as Aldrich Chemicals (Milwaukee, Wis.) Or are readily prepared using methods well known to those skilled in the art (e.g., generally Louis F. Fieser and Mary). Fieser, Reagents for Organic Synthesis, v . 1-19, Wiley, New York (1967-1999 editing), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. editing, Springer-Verlag, Berlin, by (Beilstein online database that contains the addendum Available) Prepared by the described method).

  For purposes of illustration, the reaction scheme described below provides important intermediates in addition to the possible routes for synthesizing compounds of the present invention. See the “Examples” section below for a more detailed description of the individual reaction steps. One skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of the invention. Although specific starting materials and reagents are shown in these schemes and discussed below, they can be readily exchanged with other starting materials and reagents to provide various derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

In the preparation of preferred compounds of the present invention, protection of the remote functionality of the intermediate (eg, primary or secondary amine) may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenyl-methyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. See TW Greene, " Protective Groups in Organic Synthesis ", John Wiley & Sons, New York, 1991, for a general description of protecting groups and their uses.

  Scheme I below illustrates a method for preparing compounds of the invention of formula (I) or (III).

As indicated above, the desired hydrazine hydrochloride can be first reacted with a polar solvent (eg, ethanol) diethyl acetylenedicarboxylate under reflux conditions to produce the pyrazolone intermediate ( 1a ). Suitable hydrazine compounds are commercially available or can be readily prepared using techniques well known to those skilled in the art. Pyrazolone derivatives can be synthesized using methods similar to those described in Acta Chemica Hungarica , 122 (3-4), 211-15 (1986). The pyrazolone ( 1a ) can then be treated with phosphorus oxychloride in a polar solvent (eg, dimethylformamide (DMF)) to produce the chloroaldehyde ( 1b ). Chloroaldehyde derivatives can be synthesized using techniques similar to those described in Journal of Heterocyclic Chemistry , 27 (2), 2434-5 (1990). Chloroaldehyde ( 1b ) reacts with alkyl or aryl organometallic reagents such as dialkyl zinc, alkyl chloride or magnesium bromide or aryl chloride or magnesium bromide to oxidize reagents such as pyridinium chlorochromate (PCC), CrO ₃ Swern oxidation conditions and others well known to chemists in the art can be used to provide intermediate alcohols that can be oxidized to ketone ( 1c ). The conditions for addition of the organometallic reagent are those described in Heterocycles , 53 (2), 381-386 (2000). This oxidation condition is described in Heterocycles , 29 (10), 381-386 (1989). The hydrazone ( 1d ) is then converted to the protected hydrazine using a method similar to that described in Pharmazie , 54 (2), 106-111 (1999), using chloroaldehyde ( 1b ) or ketone ( 1c ) as the protected hydrazine. By reacting, it can be formed from chloroaldehyde ( 1b ) or ketone ( 1c ). Preferred protecting groups include t-butylcarbamoyl, benzyl, benzyloxycarbamoyl, acetyl and the like. t-Butylcarbamoyl is preferred because deprotection is easy during cyclization. The hydrazone ( 1d ) can then be heated at 60-100 ° C. in an acidic solvent such as acetic acid, HCl or pTsOH in DMF, dioxane, or toluene to provide pyridazinone ( 1e ). Pyridazinone ( 1e ) is then reacted according to the procedure described in Tetrahedron , 56,5499 (2000) using tetrakistriphenylphosphine as a catalyst and reacting with the appropriate aryl boronic acid to give the desired aryl-substituted pyridazinone ( 1f). ) Can be provided. Other Suzuki reaction conditions can also be used to prepare arylpyridazinones ( 1f ) (see, for example, Chem. Rev. , 2457 (1995) and references therein).

Pyridazinone ( 1f ) can be readily converted to pyridazine chloride ( 1a ) by heating pyridazinone ( 1f ) in phosphorus oxychloride (undiluted) or some suitable solvent such as dichloroethane. Other halogenating reagents known in the literature (eg POBr ₃ and SOCl ₂ ) can be used to prepare halogenated pyridazines ( 1f ). Other leaving groups such as sulfonate groups (eg, triflate and mesylate) can also be prepared using methods well known to those skilled in the art and are used to make the final compounds in the above scheme. For example, chloride ( 1f ) can be prepared according to Indian Journal of Chemistry. Section B: Organic Chemistry Including Medicinal Chemistry , 29B (10), 966-9 (1990).

  Finally, chloropyridazine reacts with an amine nucleophile in the presence of a base at 25 ° C. to 100 ° C. in a suitable solvent to provide the desired aminopyridazine (I) or (III). Various types of bases can be used in this reaction. Suitable bases are triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, potassium fluoride and the like. Suitable solvents include ethanol, DMF, DMSO, toluene and the like.

Scheme II below illustrates one method for preparing the compounds of the invention of formula (II) or (IV), wherein R ³ is hydrogen.

Intermediate ( 2a ) is prepared by treating a suitable amine having the desired R ² group with trimethylaluminum under inert atmosphere conditions, followed by condensation with a suitable cyanide having the desired R ¹ group. can do. Suitable amines include substituted phenylamines (e.g., 4-chlorophenylamine, 4-fluorophenylamine, 4-bromophenylamine, 4-iodophenylamine, 4-cyanophenylamine, etc.), pyridin-2-ylamine, Pyridin-3-ylamine, pyridin-4-ylamine, substituted pyridinylamines (e.g. 2-dimethylaminopyridin-5-ylamine, 2-methoxypyridin-5-ylamine, 5-chloropyridin-2-ylamine, 5-methyl Pyridin-2-yl, 5-methoxypyridin-2-ylamine, 3-chloropyridin-4-ylamine, 2-N-morpholinylpyridin-5-yl, etc.) and other commercially available Or easily synthesized, substituted or unsubstituted arylamines and heteroarylamines. Suitable cyano compounds include substituted benzonitriles (e.g., 2-chlorobenzonitrile, 2-fluorobenzonitrile, 2-methoxybenzonitrile, 2-methylbenzonitrile, 2,4-dichlorobenzonitrile, 2,4- Difluorobenzonitrile, 2-chloro-4-fluorobenzonitrile, 2-chloro-4-methylbenzonitrile, 2,4-dimethoxybenzonitrile, 2-methyl-4-chlorobenzonitrile, etc.), cyano-substituted pyridine (Eg, 4-cyano-3-chloropyridine) and other commercially available or easily synthesized substituted or unsubstituted aryl nitriles or heteroaryl nitriles.

The intermediate ( 2a ) is then condensed with 3-bromo-2-oxo-propionic acid ester, a procedure similar to that described in Khanna, IK et al., J. Med. Chem. , 40, 1634 (1997) . Can be used to produce cyclized 4-hydroxy-4,5-dihydro-1H-imidazole ester Ib . For example, the amidine intermediate ( 2a ) is refluxed in a polar solvent (eg, isopropanol) in the presence of a mild base (eg, sodium bicarbonate). In general, this reaction (ie, dehydration after cyclization) proceeds directly to the desired imidazole ester intermediate ( 2c ). In some cases, dehydration of the carbinol condensation product 2b with an acid catalyst (eg, toluene sulfonic acid in refluxing toluene) may be necessary to provide the desired imidazole ester ( 2c ).

The imidazole ester ( 2c ) can be prepared from the 4-hydroxy-4,5-dihydro intermediate ( 2b ) using standard dehydration techniques well known to those skilled in the art. For example, intermediate ( 2b ) can be treated with p-toluenesulfonic acid monohydrate in refluxing toluene. Alternatively, intermediate ( 2b ) can be reacted with methanesulfonyl chloride in the presence of a base (eg, triethylamine).

The intermediate ( 2d , where L ¹ is a halogen) is obtained from the imidazole ester ( 2c ) using a halogenating reagent such as bromine, N-bromosuccinimide, iodine, or N-iodosuccinamide, and glacial acetic acid or It can be synthesized in a suitable protic solvent such as trifluoroacetic acid or an aprotic solvent such as acetonitrile, ether or THF at a reaction temperature range of 35 ° C to 100 ° C. In a preferred example, intermediate ( 2c ) is treated at room temperature with bromine in glacial acetic acid. Using an alkyl lithium base, preferentially n-BuLi or tert-butyl lithium, or an alkyl Grignard reagent such as MeMgBr or EtMgBr in a protic, aprotic solvent such as diethyl ether, dioxane or THF, A metal exchange reaction of ( 2d ) in the reaction temperature range of −100 ° C. to −78 ° C. followed by treatment with a formyl equivalent such as DMF, formylpiperidine, or ethyl formate provides the aldehyde derivative ( 2e ). Alternatively, ( 2e ) is a treatment with POCl ₃ or POBr _{3 in} a solvent such as DMF at a reaction temperature range of 35 ° C. to 100 ° C. followed by hydrolysis, or an aprotic such as CH ₂ Cl ₂ or dichloroethane. It can be prepared directly from ( 2c ) by the preparation of several equivalents of Vilsmeier reagent (POCl ₃ or POBr _{3 in} DMF) in a neutral solvent followed by hydrolysis.

The aldehyde intermediate ( 2e ) can also be synthesized by another route shown in Scheme III below.

Intermediate ( 2a ) is condensed with a 3-bromo-4-hydroxy-2-oxo-butyric acid alkyl ester derivative with an appropriate protecting group on the 4-hydroxyl substituent to give the cyclized intermediate ( 3b ). Which can be dehydrated as described above to give the imidazolyl intermediate ( 3c ). The protecting group (Pg) on the 5-hydroxymethyl group of intermediate ( 3c ) can subsequently be removed by standard techniques well known to those skilled in the art. Then intermediate (3d) is, Tett. Lett., 35, 9391-4 (1994) or J. Het. Chem., Using an oxidation technique similar to that described in 39,841-844 (2002), (2e ). For example, 5-hydroxymethyl-imidazolylmethyl derivative (3d) is a halogenated solvent such as CH ₂ Cl ₂ or CHCl _3, oxalyl chloride, is treated with a tertiary amine base such as DMSO and triethylamine or diisopropylethylamine. Alternatively, the intermediate ( 3d ) is oxidized with MnO _{2 in a} polar or non-polar solvent such as MeOH, acetone, dioxane, ether, CH ₂ Cl ₂ or CHCl ₃ .

1,2-dihydro-imidazo [4,5-d] pyridazin-4-one heterocycles such as ( 2g ) are described in Chem. Pharm. Bull ., 50,754-759 (2002) or J. Org. Chem. , 57 Can be prepared from intermediates such as ( 2e ) using procedures similar to those described in US Pat. In a preferred example, the aldehyde intermediate ( 2e ) is in the presence of a suitable acid catalyst such as acetic acid or sulfuric acid in a non-polar solvent such as benzene, toluene, xylene, or chlorobenzene, at a temperature range of 50 ° C to 130 ° C. Treated with aqueous hydrazine at ° C. The hydrazonomethyl intermediate ( 2f ) is sometimes isolated and in the presence of an acid catalyst such as acetic acid, in a non-polar solvent such as benzene, toluene, xylene, or chlorobenzene, the temperature range 80 ° C to 130 ° C. Is converted to the desired intermediate ( 2 g ). A mono-protected hydrazine derivative such as tert-butylcarbazate is used in place of hydrazine in the initial condensation reaction, but the tert-butyl protecting group must be removed using standard techniques.

Conversion of 1,5-dihydro-imidazo [4,5-d] pyridazin-4-one intermediate ( 2g ) to 4-halo-1H-imidazo [4,5-d] pyridazine intermediate ( 2h ) Halogenation in an inert solvent such as toluene, xylene, dioxane, in the presence or absence of a base (e.g., triethylamine, diisopropylethylamine, pyridine, N, N-diethylaniline) in the temperature range of -40 ° C to 200 ° C. agents _{(e.g., SOCl 2, POCl 3, PCl} 3, PCl 5, POBr 3, PBr 3, PBr 5, or PPh ₃ / NBS) may be realized by by the processing. If the halogenating agent is used in excess, it may be used as a solvent. In a preferred example, intermediate (2 g) is under reflux conditions, is processed by POCl _3.

R ⁴ is, for the compounds of the present invention such that one or more substituted with a substituent an amino group described to amino groups, or the previous formula (IA), R ⁴ includes an intermediate member (2h) It can be introduced by a coupling reaction between the corresponding amino compounds (R ⁴ —H) to produce the final compound. For example, the intermediate ( 2h ) is generally stirred with the desired amine (R ⁴ —H). The amine acts as a solvent (eg, butylamine, morpholine, pyrrolidine), or a solvent (eg, methylene chloride, N, N-dimethylformamide) is added to aid solubilization of the reactants, and / or Or it can be added to provide a medium having a suitable reflux temperature to complete the substitution. This reaction can be heated to facilitate this process. Suitable reaction temperatures are in the range of about -40 ° C to 100 ° C, and preferably run at about 30 ° C. In addition, a suitable base (eg, triethylamine, diisopropylethylamine) can be used to quench the acid produced in this process. Suitable amino compounds are purchased commercially or can be readily prepared using standard techniques well known to those skilled in the art. Preferred amino compounds (R ⁴ —H) include 4-alkylaminopiperidine-4-carboxamide (Scheme V) and 3-alkylaminoazetidine-3-carboxamide, as described below.

Compounds of formula (II) or (IV) (wherein R ³ = alkyl or aryl) can be prepared by the route shown in Scheme IV.

Intermediate (4e) is in the temperature range -100 ° C. ~0 ° C., THF, an aprotic solvent polarity, such as diethyl ether or dioxane, prepared as described in Intermediate (2d) (previously ) Lithium anions and suitable acylating agents such as esters, amides or acyl chloride derivatives. The intermediate ( 4e ) is then converted to Scheme II for the preparation of a compound of formula (II) or (IV) (wherein R ³ = H) (ie a compound of formula Il-A or IV-A). Conversion to a compound of formula (II-B) or (IV-B) in the same manner as previously described (wherein R ³ = alkyl or aryl derivative).

The compounds of the present invention (wherein R ⁴ is a primary or secondary amine) are alkylated, sulfonated and / or acylated using standard techniques well known to those skilled in the art to provide additional derivatives. (Eg, alkylamines, dialkylamines, sulfonamides, amides, carbamates, ureas, etc.) can be provided.

Many amine compounds of formula (IA) are available from commercial suppliers or are prepared by known methods readily available to those skilled in the art. The preparation of representative amine compounds of formula (IA) is illustrated in the examples below. Preparation of 4-aminopiperidine-4-carboxamide groups of formula (IA) and 4-amino-4-cyanopiperidine groups of formula (IA) and their benzyl protected precursors are described in US Pat. No. 3,161,644 to PAJ Janssen. No., C. van de Westeringh et al . , J. Med. Chem. , 7,619-623 (1964), and KA Metwally et al . , J. Med. Chem. , 41,5084-5093 (1998), where And the 4-amino group is an unsubstituted, monosubstituted, or disubstituted heterocyclic ring, or a part thereof. Related bicyclic derivatives are described in K. Frohlich et al., Tetrahedron , 54, 13115-13128 (1998) and references contained therein. Spiro-substituted piperidines of formula (IA) are described in PAJ Janssen, U.S. Pat.No. 3,155,670, KA Metwally et al . , J. Med Chem. , 41, 5084-5093 (1998), T. Toda et al . , Bull. Soc. Japan , 44, 3445-3450 (1971), and W. Brandau and S. Samnick, WO 9522544. The preparation of 3-aminoazetidine-3-carboxamide is described by AP Kozikowski and AH Fauq Synlett , 783-784 (1991). The preparation of a preferred 4-alkylamino-piperidine-4-carboxamide group of formula (IA) is shown in Scheme V below. The corresponding 3-alkylaminoazetidine-3-carboxamide and 3-alkylaminopyrrolidine-3-carboxamide can be prepared in a similar manner. Spiro-substituted derivatives can be used in a manner similar to that contained in the above references.

The amino group of 4-piperidinone is first protected to provide the intermediate ( 5a ). A useful protecting group is benzyl. 4-Piperidinones and their derivatives can be purchased commercially from various suppliers (eg, Interchem Corporation, Paramus, NJ and Sigma-Aldrich Co., St. Louis, MO). Piperidinone ( 5a ) is then reacted with the desired alkylamine and potassium cyanide in an aqueous HCl / ethanol solvent mixture at about 0 ° C. to about 30 ° C. to produce the cyano intermediate ( 5b ). The cyano group is converted to the corresponding amide with acid and water. The protecting group is then removed using conventional methods for the particular protecting group used. For example, a benzyl-protecting group can be removed by hydrogenation in the presence of Pd / C.

For these compounds of the invention (wherein R ⁴ is an unsubstituted or substituted alkoxy group), the intermediate ( 2h or 4h ) is a base (eg potassium t-butoxide) and aprotic It can be treated with the desired alcohol in the presence of a solvent (eg, THF). Suitable alcohols can be purchased commercially or readily prepared using standard techniques well known to those skilled in the art.

  Conventional methods and / or techniques of separation and purification known to those skilled in the art can be used to isolate various intermediates associated with them in addition to the compounds of the present invention. Such techniques are well known to those skilled in the art and include, for example, all types of chromatography (high performance liquid chromatography (HPLC), column chromatography using common adsorbents such as silica gel, and thin layer Chromatography), recrystallization, and differential (ie, liquid-liquid) extraction techniques.

The compounds of the invention are isolated and used per se or in the form of pharmaceutically acceptable salts, solvates and / or hydrates thereof. The term “salt” means inorganic and organic salts of the compounds of the invention. These salts may be reacted in situ or during the final isolation and purification of the compound, individually with the appropriate organic or inorganic acid or base, and the salt thus formed. It can be prepared by releasing. Representative salts include hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfite, nitrate, acetate, trifluoroacetate, oxalate, benzene sulfonate (besylate), Palmitate, pamoate, malonate, stearate, laurate, malate, borate, lactate, phosphate, hexafluorophosphate, mesylate, benzoate, tosyl Including acid, formate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, glucoheptonate, lactobionate, laurylsulfonate, etc. . A preferred salt of the compound of the invention is the hydrochloride salt. These salts include cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, Including non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ethylamine and the like. See, for example, Berge et al., J. Pharm. Sci. , 66, 1-19 (1977).

  The term “prodrug” refers to a compound of formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt, hydrate or solvate of this compound, in It means a compound that is converted in vivo. This conversion can occur by various mechanisms such as hydrolysis in the blood. A discussion of the use of prodrugs can be found in T. Higuchi and W. Stella, “Pro-Drugs as Novel Delivery Systems”, Vol. 14, ACS Symposium Series, and “Bioreversible Carriers in Drug Design”, edited by Edward B. Roche, American It is shown in Pharmaceutical Association and Pergamon Press, 1987.

For example, the compounds of the present invention contain a carboxylic acid functional group and the prodrug is a (C ₁ -C ₈ ) alkyl, (C ₂ -C ₁₂ ) alkanoyloxymethyl, 4-9 of the hydrogen atom of the acid group. 1- (alkanoyloxy) ethyl having carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 4 to 1- (alkoxycarbonyloxy) ethyl having 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, N- (having 3 to 9 carbon atoms) Alkoxycarbonyl) aminomethyl, 1- (N- (alkoxycarbonyl) amino) ethyl having 4-10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactone-4-yl, di-N , N- (C ₁ -C ₂ ) alkylamino (C ₂ -C ₃ ) alkyl (e.g., β- Dimethylaminoethyl), carbamoyl- (C ₁ -C ₂ ) alkyl, N, N-di (C ₁ -C ₂ ) alkylcarbamoyl- (C ₁ -C ₂ ) alkyl and piperidine-, pyrrolidino- or morpholino (C ₂ Esters formed by substitution with groups such as -C ₃ ) alkyl may be included.

Similarly, when the compound of the present invention contains an alcohol functional group, the prodrug is substituted with a hydrogen atom of the alcohol group, (C ₁ -C ₆ ) alkanoyloxymethyl, 1-((C ₁ -C ₆ ) alkanoyloxy) Ethyl, 1-methyl-1-((C ₁ -C ₆ ) alkanoyloxy) ethyl, (C ₁ -C ₆ ) alkoxycarbonyloxymethyl, N- (C ₁ -C ₆ ) alkoxycarbonylaminomethyl, succinoyl, C ₁ -C ₆ ) alkanoyl, α-amino (C ₁ -C ₄ ) alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is natural L- amino acids are selected from _{P (O) (OH) 2} , P (O) (O (C 1 -C 6) alkyl) ₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal of a carbohydrate) The

The compounds of the present invention incorporate an amine functional group and the prodrugs are R-carbonyl, RO-carbonyl, NRR′-carbonyl (where R and R ′ are each independently (C ₁ -C ₁₀ ) alkyl). , (C ₃ -C ₇ ) cycloalkyl, benzyl), or the like, or R-carbonyl can be a natural α-aminoacyl or a natural α -Aminoacyl-natural-α-aminoacyl, -C (OH) C (O) OY '(where Y' is H, (C ₁ -C ₆ ) alkyl or benzyl, -C (OY ₀ ) Y ₁ Wherein Y ₀ is (C ₁ -C ₄ ) alkyl), and Y ₁ is (C ₁ -C ₆ ) alkyl, carboxy (C ₁ -C ₆ ) alkyl, amino (C _1- C ₄ ) alkyl or mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoalkyl, -C (Y ₂ ) Y ₃ (where Y ₂ is H or methyl; and Y ₃ is mono -N- or di _{-N, N- (C 1 -C 6} ) alkylamino , Morpholino, piperidin-1-yl or pyrrolidin-1-yl.).

  The compounds of the present invention may contain asymmetric or chiral centers and consequently exist in different stereoisomeric forms. In addition to all stereoisomeric forms of the compounds of the invention, those mixtures including the racemic mixtures are intended to form part of the invention. In addition, the present invention encompasses all geometric and positional isomers. For example, when a compound of the present invention incorporates a double bond or fused ring, mixtures in addition to both cis- and trans- forms are included within the scope of the present invention. Both single regioisomers and mixtures of regioisomers arising from N-oxidation of the heteroaromatic ring nitrogen are within the scope of the present invention.

  Diastereomeric mixtures can be separated into their individual diastereoisomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers react with appropriate optically active compounds (e.g. chiral alcohols or chiral auxiliary such as Mosher acid chloride), separation of diastereoisomers, and correspondence of individual diastereoisomers. Can be separated by conversion of the enantiomeric mixture to a diastereomeric mixture by conversion to the pure enantiomer (eg hydrolysis). Also, some of the compounds of the present invention are atropisomeric (eg, substituted biaryls) and can be considered part of the present invention. Enantiomers can also be separated by use of chiral HPLC column.

  The compounds of the present invention can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention relates to solvated and unsolvated forms. It is intended to encompass both.

  The compounds of the invention can exist in different tautomeric forms, and all such forms can be embraced within the scope of the invention. For example, all tautomeric forms of the triazinone moiety are included in the present invention. For example, all keto-enol and imine-enamine forms of the compounds are included in the present invention.

The present invention further provides the same as cited herein, apart from the fact that one or more atoms are replaced by an atom having an atomic weight or atomic number different from the normally recognized atomic weight or atomic number. Isotope-labeled compounds of the present invention. Examples of isotopes that can be incorporated into the compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, eg, ² H, ³ H, ¹¹ C, ¹³ C, ^{14, respectively.} C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I, and ³⁶ Cl.

Certain isotopically-labeled compounds of the present invention (eg, those labeled with ³ H and ¹⁴ C) are useful in compound and / or substrate tissue distribution assays. Tritiated (ie ³ H) and carbon-14 (ie ¹⁴ C) isotopes are particularly preferred because of their easy preparation and detectability. In addition, replacement with heavier isotopes such as diuterium (i.e. ² H) has certain therapeutic advantages resulting from greater metabolic stability (e.g., extended in vivo half-life or reduced required dose), and Results May be preferred in some environments. Positron emitting isotopes, such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F, are useful for positron emission tomography (PET) to test substrate receptor occupancy. Isotopically-labeled compounds of the present invention are generally similar in procedure to those described in the following schemes and / or examples herein by replacing non-isotopically labeled reagents with isotope-labeled reagents. Can be prepared according to

  Another aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or an effective amount of a compound of the invention and a pharmaceutically acceptable excipient, diluent, or carrier. A method of treating a disease, condition and / or disorder modulated by a cannabinoid receptor antagonist in an animal comprising administering to the animal in need of such treatment. This method is particularly useful for treating diseases, symptoms and / or disorders modulated by cannabinoid receptor (especially CB1 receptor) antagonists.

  Preliminary studies point out that the following diseases, symptoms, and / or disorders are modulated by cannabinoid receptor antagonists: eating disorders (eg, overeating, anorexia, and bulimia), weight loss Or management (e.g. reduced calorie or food intake and / or appetite suppression), obesity, depression, atypical depression, bipolar disorder, psychosis, schizophrenia, behavioral epilepsy, suppression of reward-related behavior (e.g. conditioning (E.g. suppression of cocaine- and morphine-induced conditioned place preference), substance abuse, dependence disorders, urges, alcohol addiction (e.g. withdrawal symptoms, reduced cravings, and recurrence of alcohol consumption) Treatment of alcohol abuse, epilepsy and / or dependence, including prevention), tobacco abuse (e.g., smoking epilepsy, smoking cessation and / or dependence, including reduced smoking craving and prevention of recurrence) Treatment), dementia (including memory loss, Alzheimer's disease, aging dementia, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild neurocognitive impairment), male sexual dysfunction (e.g. Dysfunction), convulsions, epilepsy, inflammation, gastrointestinal disorders (e.g., gastrointestinal motility or forward-promoting dysfunction), attention deficit disorders (ADD, including attention deficit hyperactivity disorder (ADHD)), Parkinson Disease, and type II diabetes. Accordingly, the compounds of the invention described herein are useful in treating diseases, conditions or disorders modulated by cannabinoid receptor antagonists. As a result, the compounds of the present invention (including the compositions and processes used herein) can be used in the manufacture of a medicament for the therapeutic uses described herein.

  Other diseases, symptoms and / or disorders for which cannabinoid receptor antagonists may be effective include: premenstrual or late luteal syndrome, migraine, panic disorder, anxiety, posttraumatic syndrome, social phobia Cognitive dysfunction in non-demented individuals, mild cognitive impairment of non-amnestics, postoperative cognitive decline, impulsive behavior related disorders (e.g. disruptive behavior disorders (e.g. anxiety / depression, executive function improvement, tic disorders, Behavioral disorder and / or opposite challenging disorder), adult personality disorder (eg borderline personality disorder and antisocial personality disorder), related diseases with impulsive behavior (eg substance abuse, paraphilia, and multiple personality), and impulse Dysregulation (e.g. intermittent explosive disorder, theft, arson, gambling, and hair removal), obsessive compulsive disorder, chronic fatigue syndrome, male sexual dysfunction (e.g. premature ejaculation), female sexual function Dysfunction, sleep disorders (e.g. sleep apnea), autism, speechlessness, neurodegenerative movement disorders, spinal cord injury, central nervous system damage (e.g. trauma), seizures, neurodegenerative diseases or toxic or infectious CNS diseases (eg encephalitis or meningitis), cardiovascular disorders (eg thrombosis) and diabetes.

  Accordingly, the compounds of the invention described herein are useful in the treatment of diseases, conditions or disorders modulated by cannabinoid receptor antagonists. Consequently, the compounds of the invention (including the compositions and processes used herein) can be used in the manufacture of a medicament for the therapeutic uses described herein.

  The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.7 mg to about 7,000 mg / day. Typically, for a normal adult weighing about 70 kg, a dose in the range of about 0.01 mg to about 100 mg / kg body weight is sufficient. However, some variability in the general dosage range may be necessary depending upon the age and weight of the subject being treated, the intended route of administration, the particular compound being administered and the like. Determination of dosage ranges and dosages for a particular patient is within the ability of those skilled in the art with the benefit of the present disclosure. The compounds of the present invention can be used in sustained release, controlled release, and delayed release formulations, and these forms are also well known to those skilled in the art.

The compounds of the present invention can be used in combination with other pharmaceutical agents for the treatment of the diseases, symptoms and / or disorders described herein. Accordingly, there is also provided a method of treatment comprising administering a compound of the present invention in combination with other pharmaceutical agents. Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention are anti-obesity agents such as apolipoprotein-B secretion / microsomal triglyceride transfer protein (apo-B / MTP) inhibitors, 11β-hydroxysteroid dehydrogenase-1 (11β-HSD type 1) inhibitor, peptide YY _3-36 or analogs thereof, MCR-4 agonist, cholecystokinin-A (CCK-A) agonist, monoamine reuptake inhibitor (such as sibutramine), sympathetic nerve action Drugs, β ₃ adrenergic receptor agonists, dopamine agonists (such as bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c agonists, melanin-concentrating hormone antagonists, leptin (OB protein), leptin analogs, leptin receptor agonists, Galanin antagonist, lipase inhibitor (tetrahydrolipsta Such as orlistat), appetite suppressants (such as bombesin agonists), neuropeptide-Y receptor antagonists (eg, NPY Y5 receptor antagonists, such as US Pat. Nos. 6,566,367; 6,649,624; 6,638,942; No. 6,495,559; No. 6,462,053; No. 6,388,077; No. 6,335,345; and No. 6,326,375; US Patent Publication Nos. 2002/0151456 and 2003/036652; and PCT Publication No. WO 03/010175 , Spiro compounds disclosed in WO 03/082190 and WO 02/048152), thyroid mimetics, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin Receptor antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (e.g. AxokineTM, Regeneron Pharmaceutica ls, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti-related protein (AGRP), ghrelin receptor antagonist, histamine 3 receptor antagonist or inverse agonist, and neuromedin U receptor Including body agonists. Other anti-obesity agents, including the preferred materials described below, are well known or will be readily apparent to those of skill in the art in view of the present disclosure.

Particularly preferred are orlistat, sibutramine, bromocriptine, ephedrine, leptin, pseudoephedrine; peptide YY _3-36 or analogs thereof; and 2-oxo-N- (5-phenylpyrazinyl) spiro- [ An anti-obesity drug selected from the group consisting of isobenzofuran-1 (3H), 4′-piperidine] -1′-carboxamide. Preferably, the compounds of the invention and combination therapies are administered in combination with exercise and a reasonable diet.

Representative anti-obesity agents for the combined uses, pharmaceutical compositions, and methods of the invention can be prepared using methods known to those skilled in the art, for example, sibutramine is described in US Pat. No. 4,929,629. Bromocriptine is prepared as disclosed in US Pat. Nos. 3,752,814 and 3,752,888; orlistat is prepared in US Pat. Nos. 5,274,143; 5,420,305; 5,540,917; Prepared as disclosed; P YY _3-36 (including analogs) was prepared as disclosed in US 2002/0141985 and WO 03/027637; and NPY Y5 The receptor antagonist 2-oxo-N- (5-phenylpyrazinyl) spiro [isobenzofuran-1 (3H), 4′-piperidine] -1′-carboxamide is disclosed in US Patent Publication No. 2002/0151456. As prepared. Other useful NPY Y5 receptor antagonists include 3-oxo-N- (5-phenyl-2-pyrazinyl) -spiro [isobenzofuran-1 (3H), 4′-piperidine] -1′-carboxamide; -Oxo-N- (7-trifluoromethylpyrido [3,2-b] pyridin-2-yl) -spiro- [isobenzofuran-1 (3H), 4'-piperidine] -1'-carboxamide N -[5- (3-Fluorophenyl) -2-pyrimidinyl] -3-oxospiro- [isobenzofuran-1 (3H), [4'-piperidine] -1'-carboxamide;trans-3'-oxo-N -(5-Phenyl-2-pyrimidinyl)] spiro [cyclohexane-1,1 '(3'H) -isobenzofuran] -4-carboxamide; trans-3'-oxo-N- [1- (3-quinolyl) ) -4-Imidazolyl] spiro [cyclohexane-1,1 ′ (3′H) -isobenzofuran] -4-carboxamide; trans-3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [4- Azaiso-benzofuran-1 (3H), 1'-cyclohexane] -4'-carboxyami Trans-N- [5- (3-Fluorophenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide; trans-N -[5- (2-Fluorophenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxamide; trans-N- [1- (3,5-difluorophenyl) -4-imidazolyl] -3-oxo-spiro (7-azaisobenzofuran-1 (3H), 1'-cyclohexane) -4'-carboxamide; trans-3-oxo-N -(1-phenyl-4-pyrazolyl) spiro [4-azaisobenzofuran-1, (3H), 1'-cyclohexane] -4'-carboxamide; trans-N- [1- (2-fluorophenyl)- 3-pyrazolyl] -3-oxospiro [6-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide; trans-3-oxo-N- (1-phenyl-3-pyrazolyl) spiro [6-Azaisobenzofuran-1 (3H), 1'-cyclohex San] -4'-carboxamide; trans-3-oxo-N- (2-phenyl-1,2,3-triazol-4-yl) spiro [6-azaisobenzofuran-1 (3H), 1'- Cyclohexane] -4'-carboxamides; and pharmaceutically acceptable salts and esters thereof, such as those disclosed in PCT Publication No. 03/082190. All previously cited US patents and publications are incorporated herein by reference.

  Other suitable pharmaceutical agents that can be administered in combination with the compounds of the present invention are substances designed to treat tobacco abuse (e.g., the nicotine receptor partial agonist, bupropine hydrochloride (also known as ZybanTM)). ) And nicotine replacement therapies), substances that treat erectile dysfunction (e.g., dopamine agonists such as apomorphine), ADD / ADHD drugs (e.g., Ritalin (TM), Strattera (TM), Concerta (TM) and Adderall (TM) )), And substances that treat alcoholism such as opioid antagonists (e.g., naltrexone (also known as ReVia) and nalmefene), disulfiram (also known as Antabuse), and acamprosate (also known as Campral (TM)) Known)). In addition, substances that reduce alcohol withdrawal symptoms, such as benzodiazepines, β-blockers, clonidine, carbamazepine, pregabalin, and gabapentin (Neurontin ™) can also be co-administered. Treatment of alcohol addiction is preferably administered with behavioral therapy, including components such as motivational augmentation therapy, cognitive behavioral therapy, and so-called self-help groups, including Alcohol Anonymous (AA).

Other pharmaceuticals that are useful include antihypertensive drugs (eg, COX-2 inhibitors); antiepileptic drugs (eg, fluoxetine hydrochloride (Prozac ™)); cognitive enhancers (eg, donepezil hydrochloride (Aircept ™)) and others Neuroprotective drugs (eg nemantine); antipsychotics (eg ziprasidone (Geodon ™), risperidone (Risperdal ™), and olanzapine (Zyprexa ™); insulin and insulin analogues ( For example, LysPro insulin); GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36) -NH ₂ ; sulfonylureas and their analogs; chlorpropamide, glibenclamide, tolbutamide, tolazamide , Acetohexamide, Glypizide®, glimepiride, repaglinide, meglitinide; biguanide, metflumin, phenfuramine, buformin; α2-antagonis And imidazoline: midagizole, isaglidol, deliglidol, idazoxan, efaloxane, fluparoxane; other insulin secretagogues: linoglylide, A-4166; glitazone: siglitazone, Actos® (pioglitazone), englitazone, troglitazone, dalglitazone, Avandia (Registered trademark) (BRL49653); fatty acid oxidation inhibitor: chromoxyl, etomoxil; α-glucosidase inhibitor: acarbose, miglitol, emigrate, voglibose, MDL-25,637, camiglibose, MDL-73,945; β-agonist: BRL 35135, BRL 37344 , RO 16-8714, ICI D7114, CL 316,243; phosphodiesterase inhibitors: L-386,398; lipid-lowering drugs: benfluorex: fenfluramine; vanadate and vanadium complexes (eg Naglivan®) and peroxo Vanadium complexes; amylin antagonists; glucagon antagonists; gluconeogenesis inhibitors; somatostatin analogs; antilipolytics: nicotinic acid, acipimox, WAG 994, pramlintide (Symlin ™), AC 2993, nateglinide, aldose reductase inhibitors (eg, , Zopolrestat), glycogen kinase inhibitor, sorbitol dehydrogenase inhibitor, sodium-hydrogen exchange type 1 (NHE-1) inhibitor and / or cholesterol biosynthesis inhibitor or cholesterol absorption inhibitor, especially HMG-CoA reductase inhibitor Drugs (e.g., atorvastatin or their hemi-calcium salts), or HMG-CoA synthase inhibitors, or HMG-CoA reductase or synthase gene expression inhibitors, CETP inhibitors, bile acid sexual esters, fibric acid, ACAT inhibitor, squalene synthase inhibitor, antioxidant or Contains iacin. The compounds of the present invention can also be administered in combination with natural compounds that act to lower plasma cholesterol levels. Such natural compounds are commonly referred to as nutritional supplements and include, for example, garlic extract, Hoodia plants, and niacin.

  The dose of the additional medicinal product (e.g. anti-obesity agent) will generally depend on the health of the subject being treated, the degree of treatment desired, the nature and type of combination therapy, if any, and the frequency of treatment and nature of the desired effect Will depend on many factors, including In general, the dose range of anti-obesity agents is in the range of about 0.001 mg to about 100 mg / kg body weight / day, preferably about 0.1 mg to about 10 mg / kg body weight / day. However, some variation in the general dosage range is also necessary depending on the age and weight of the subject being treated, the intended route of administration, the particular anti-obesity agent being administered, and the like. Determination of dosage ranges and appropriate amounts for a particular patient is also within the ability of those skilled in the art having the benefit of this disclosure.

  As mentioned above, the compounds of the present invention are useful in the treatment of diseases, conditions and / or disorders modulated by cannabinoid receptor antagonists; therefore, another aspect of the present invention is the therapeutic treatment of compounds of the present invention. A pharmaceutical composition comprising an effective amount and a pharmaceutically acceptable excipient, diluent or carrier. Alternatively, the compounds of the present invention can be administered in combination with at least one additional pharmaceutical agent (also referred to herein as “combination”) that is also preferably administered in the form of a pharmaceutical composition. The compounds or combinations of the present invention may be used in conventional oral, rectal, transdermal, parenteral (e.g., intravenous, intramuscular, or subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, topical (e.g., powders) , Ointments, or droplets), or oral or nasal dosage forms. In the combination aspect of the present invention, the compound of the present invention and at least one other pharmaceutical agent (e.g., the anti-obesity agents described above) are either individually or as a pharmaceutical composition containing both. Can be administered. It is generally preferred that such administration be oral. However, parenteral or transdermal administration is suitable if the subject being treated is incapable of swallowing or oral administration is otherwise impaired or undesirable.

  When administered in combination, such administration can be at successive time points or simultaneously, with simultaneous methods generally being preferred. For sequential administration, the combinations can be administered in any order. In general, such administration is preferably oral. It is particularly preferred that such administration be oral and simultaneous. When the combination is administered sequentially, the administration of the compound of the invention and the additional pharmaceutical agent can be in the same or different ways.

  A typical formulation is prepared by mixing a compound of the present invention and an excipient, diluent or carrier. Suitable excipients, diluents and carriers are well known to those skilled in the art and include carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water Including materials such as. The particular excipient, diluent or carrier used will depend upon the means and purpose for which the compound of the present invention is being applied. The solvent is generally selected based on solvents (GRAS) that are recognized as safe for administration to mammals by those skilled in the art. Generally safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (eg, PEG400, PEG300), and the like, and mixtures thereof. These preparations can be one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing agents. Refined provision of drugs (i.e. compounds of the present invention or pharmaceutical compositions thereof) or pharmaceutical products (including auxiliaries, colorants, sweeteners, flavorings, flavoring agents, and other known additives) That is, it assists in the manufacture of pharmaceuticals. These preparations can be prepared by ordinary dissolution and mixing techniques. For example, a bulk drug substance (i.e., a compound of the invention or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) may be one or more of the aforementioned excipients. It is dissolved in a suitable solvent in the presence of the agent.

  Compositions suitable for parenteral injection generally comprise a pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion. These compositions generally contain a sterile excipient, diluent or carrier for reconstitution of a sterile injectable solution or dispersion. Examples of suitable aqueous and non-aqueous excipients, diluents or carriers are water, ethanol, polyols (such as propylene glycol, polyethylene glycol, glycerol), suitable mixtures thereof, vegetable oils (such as olive oil) and ethyl oleate Such as injectable organic esters. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, or by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

  These compositions may contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial contamination of the composition can be achieved with various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and the like. For example, it may be desirable to include isotonic agents such as sugars and sodium chloride. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of substances capable of delaying absorption, for example, aluminum monostearate and gelatin.

  Solid dosage forms for oral administration include capsules, tablets, powders and granules. In such solid dosage forms, the compounds or combinations of the present invention are mixed with at least one pharmaceutically acceptable excipient, diluent or carrier. Suitable excipients, diluents, or carriers are sodium citrate or dicalcium phosphate, or (a) a filler or bulking agent (eg, starch, lactose, sucrose, mannitol, silicic acid, etc.); ) Binders (eg carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, acacia gum etc.); (c) humectants (eg glycerol etc.); (d) disintegrants (eg agar-agar, calcium carbonate) Potato starch or tapioca starch, alginic acid, some complex silicic acid, sodium carbonate, etc.); (e) liquid retarders (eg paraffin etc.); (f) absorption enhancers (eg quaternary ammonium compounds etc.); (g) Wetting agents (eg cetyl alcohol, glycerol monostearate, etc.); (h) adsorbents (eg kaolin, bentonite, etc.); and / or (i) lubricants (E.g. talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate). In the case of capsules and tablets, these dosage forms can also contain buffering agents.

  Similar types of solid compositions can also be used as fillers in soft or hard-filled gelatin capsules using high molecular weight polyethylene glycols and the like in addition to excipients such as lactose or milk sugar.

  Solid dosage forms such as tablets, dragees, capsules, and granules can be prepared with enteric coatings and other coatings and shells well known in the art. These can also include opacifiers and can be such compositions that release the compounds of the invention and / or additional pharmaceutical agents in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The drug can also be in micro-encapsulated form, if appropriate, with one or more of the aforementioned excipients.

  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to a compound or combination of the present invention, liquid dosage forms can include excipients, diluents, or carriers. Suitable excipients, diluents or carriers are water or, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil content Other solvents, such as, for example, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, mixtures of these substances, etc. Contains additives such as solubilizers and emulsifiers. Other suitable additives (ie, excipients, diluents or carriers) include wetting agents, emulsifying and suspending agents, sweetening, flavoring, and flavoring agents.

  In addition to the compounds or combinations of the present invention, the suspending agent can further comprise ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and Suspending agents such as tragacanth or a mixture of these substances can be included.

  A composition for rectal or vaginal administration preferably comprises a suppository, which is a compound or combination of the invention, usually solid at room temperature and liquid at body temperature, and thus melts in the rectal or vaginal cavity. Can be prepared by mixing with a suitable non-irritating excipient, diluent or carrier such as cocoa butter, polyethylene glycol or suppository waxes which releases the active ingredient (s).

  Dosage forms for external administration of the compounds of the invention and combinations of the compounds of the invention with anti-obesity agents can include ointments, powders, sprays and inhalants. These drugs can be mixed under sterile conditions with pharmaceutically acceptable excipients, diluents or carriers and any preservatives, buffers or propellants that may be required. Ophthalmic formulations, ophthalmic ointments, powders, and solutions are also intended to be included within the scope of the present invention.

  The compounds or combinations of the present invention are typically formulated into pharmaceutical dosage forms to provide an easily controllable dose of the drug, as well as providing a patient with a sophisticated and easily handleable product. The pharmaceutical composition (or formulation) for application can then be packaged in a variety of ways depending on the method used for drug administration. In general, merchandise for distribution includes a container in which is placed a suitably shaped pharmaceutical preparation. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders and the like. The container can also include an assemblage to prevent inadvertent access to the contents of the package. In addition, the container has disposed thereon a label describing its contents. This label also includes an appropriate warning.

  The following paragraphs describe examples of formulations, dosages, etc. that are useful for non-human animals. Administration of a compound or combination of the invention (ie, a compound of the invention with at least one additional pharmaceutical agent) can act orally or parenterally (eg, by injection).

  An amount of a compound (or combination) of the invention is administered to receive an effective amount. In general, the daily dose to be orally administered to an animal is about 0.01 to about 1,000 mg / kg body weight, preferably about 0.01 to about 300 mg / kg body weight.

  Conveniently, the compound (or combination) of the invention can be carried in the drinking water so that a therapeutic dose of the compound is taken with the daily water supply. This compound can be measured directly into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water-soluble salt).

  Conveniently, the compounds (or combinations) of the present invention are also referred to as premixes or concentrates and may be added directly to the feed, as such, or to animal feed supplements. A premix or concentrate of this compound with an excipient, diluent or carrier is more commonly used to include the substance in the feed. Suitable carriers are preferably liquid or solid, such as water, various coarse flours such as alfalfa flour, soy flour, cottonseed oil flour, linseed oil flour, corn cob flour, such as those normally used in poultry feeds And corn meal, molasses, urea, bone meal, and mineral mixtures. A particularly effective carrier is each animal diet itself; that is, a small portion of such feed. This carrier facilitates the uniform distribution of the compound in the finished feed formulated with the premix. Preferably, this compound is blended entirely into the premix and subsequently into the feed. In this regard, the compound may be dispersed or dissolved in a suitable oil vehicle such as soybean oil, corn oil, cottonseed oil, or in a volatile organic solvent, and then combined with a carrier. The amount of compound in the finished feed can be adjusted by blending the feed with the appropriate proportion of premix to obtain the desired level of compound, so the proportion of compound in the concentrate is It will be understood that it can vary widely.

  High potency concentrates are formulated by feed manufacturers with proteinaceous carriers, such as soybean oil flour and other coarse flours, as described earlier, and are suitable for direct feeding to animals Concentrated adjuvants can be made. In such cases, these animals can consume a normal diet. Alternatively, such concentrated supplements can be added directly to the feed to produce a nutritionally balanced finished feed containing a therapeutically effective level of a compound of the invention. These mixtures are thoroughly formulated by standard techniques such as a biaxial shell blender to ensure homogeneity.

  If an adjuvant is used as a dressing on the surface of the feed, it will probably help ensure a uniform distribution of the compound across the surface of the dressed feed.

Drinking water and feeds that are effective in increasing red meat deposition and improving lean to fat ratio are generally sufficient to provide about 10 ^-3 to about 500 ppm of this compound in the feed or water. Prepared by mixing with an amount of animal feed.

  Preferred drug-contained pig, dairy cow, sheep and goat diets contain from about 1 to about 400 g of the compound (or combination) / ton of the invention, and the optimum amount for these animals is usually about 50 ~ 300g / ton of feed.

  Preferred poultry and domestic pet feeds usually contain from about 1 to about 400 grams, and preferably from about 10 to about 400 grams of the compound (or combination) / ton of the present invention.

  For parenteral administration in animals, the compounds (or combinations) of the present invention are prepared in the form of pastes or pellets and are usually found in animal heads where increased red meat deposition and improved lean to fat ratio are sought. Or it can be administered as an implant under the ear skin.

  Generally, parenteral administration is associated with injection of a sufficient amount of a compound (or combination) of the invention to provide the animal with about 0.01 to about 20 mg / kg / day of body weight of the drug. A preferred dose for poultry, pigs, dairy cows, sheep, goats and domestic pets is about 0.05 to about 10 mg / kg / day body weight of the drug.

  Paste formulations can be prepared by dispersing the drug in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil and the like.

  A pellet containing an effective amount of a compound, pharmaceutical composition, or combination of the present invention is prepared by combining the compound or combination of the present invention with a diluent such as carbowax, carnuba wax, and magnesium stearate or calcium stearate. Can be prepared by mixing with a lubricant added to improve the pelletizing process.

  It will be appreciated that more than one pellet may be administered to an animal to achieve the desired dosage level that provides the desired increase in red meat deposition and improved lean to fat ratio. In addition, implants can be made periodically during the animal treatment period to maintain proper drug levels in the animal's body.

  The present invention has several advantageous veterinary features. For pet owners or veterinarians who wish to increase lean and / or remove unwanted fat from pet animals, the present invention provides a means by which this can be accomplished. For poultry, cattle, and pig breeders, use of the method of the present invention results in red animals that are expected to have higher selling prices from the meat industry.

  Embodiments of the present invention are illustrated by the following examples. However, it is understood that aspects of the invention are not limited to the specific details of these examples, and that other variations thereof are known to those skilled in the art or are apparent in light of the present disclosure. I will.

  Unless otherwise specified, starting materials are generally Aldrich Chemicals Co. (Milwaukee, WI), Lancaster Synthesis, Inc. (Wynnham, NH), Acros Organic (Fair Lawn, NJ), Maybridge Chemical Company, Ltd. (Cornwell, UK) ), Tyger Scientific (Princeton, NJ), and AstraZeneca Pharmaceuticals (London, UK).

General Experimental Procedures Unless otherwise specified, all operations are carried out at room temperature or ambient temperature, ie in the range 18-25 ° C .; solvent evaporation is carried out using a rotary evaporator under reduced pressure in a bath of up to 60 ° C. The reaction was monitored by thin layer chromatography (TLC), reaction times are shown for illustrative purposes only; melting points (mp) are shown without correction (polymorphs can give different melting points) The structure and purity of all isolated compounds were confirmed by at least one of the following techniques: TLC (plate pre-coated with Merck silica gel 60 F-254), high performance liquid chromatography (HPLC), Mass spectrometry, nuclear magnetic resonance (NMR) or infrared spectroscopy (IR). Yields are shown for illustrative purposes only.

  Flash column chromatography was performed using Merck silica gel 60 (230-400 mesh ASTM). Low resolution nuclear magnetic resonance spectra (EI) data were obtained on an Automass 120 (JEOL) mass spectrometer. Liquid chromatography data was collected with a Hewlett Packard 1100 liquid chromatography / Mass Selection detector (LC / MSD). Analysis was performed on a Luna C-18 column with dimensions of 3.0x150 mm. The flow rate was 0.425 ml / min, and the gradient was 15 minutes with a gradient of 50% to 0.1% aqueous formic acid and 50% acetonitrile to 100% acetonitrile. The ionization type of the mass spectrometer mass detector was a positive ion mode, atmospheric pressure electrospray with a fragmentation voltage of 50 volts.

  Unless otherwise specified, NMR data is based on tetramethylsilane (TMS) (ppm) as an internal standard, modified chloroform (99.8% D), methanol (99.8% D) or dimethyl sulfoxide (99.9% D) as a solvent. The usual abbreviations used were as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = wide, etc.

The following abbreviations were used:
THF: tetrahydrofuran
CH ₂ Cl ₂ : Dichloromethane (DCM)
NaHCO ₃ : Sodium bicarbonate
HCl: hydrochloric acid
MgS0 ₄ : Magnesium sulfate
Na ₂ SO ₄ : Sodium sulfate
DME: Dimethoxyethane
n-BuLi: n-Butyllithium
DMF: Dimethylformamide
DCE: Dichloroethane

Preparation of key intermediates
Preparation of intermediate 5-chloro-1- (2-chloro-phenyl) -4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (1-1a):

A mixture of 2-dichlorophenyl hydrazine hydrochloride (13.4 g, 75 mmol) and diethylacetylene dicarboxylate (12.0 ml, 75 mmol) in absolute ethanol (200 ml) is treated with solid potassium carbonate (20.7 g, 150 mmol) and the resulting slurry mixture Was heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and concentrated to about 150 ml. 1N HCl (ca. 100 ml) was added to the ethanol mixture to make the mixture acidic. An additional 300 ml of water was added and the solid product precipitated as an orange solid product I-1a (17.4 g, 87%) which was isolated by filtration, washed with water and dried in the oven overnight. ¹ H NMR (400 MHz, CD ₃ 0D) δ7.62-7.46 (m, 4H), 6.00 (s, 1H), 4.35 (q, 2H), 1.36 (t, 3H); MS (m / z) 267.3 ( M +); HPLC (Method A): Retention time: 1.7 minutes.

Preparation of intermediate 5-chloro-1- (2-chloro-phenyl) -4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-1b)

N, N-dimethylformamide (5.14 ml, 4 eq) was slowly added to a solution of pyrazolone intermediate I-1a (16.37 g, 61.38 mmol) in phosphorus oxychloride (100 ml) at ˜25 ° C. (room temperature). The resulting solution was refluxed for 24 hours under nitrogen. The reaction mixture was cooled to room temperature, concentrated to about 50 ml, quenched with 800 ml ice water (caution: heat and gas evolution) and extracted with ethyl acetate (3 × 300 ml). The organic layer was dried and concentrated to give the crude product. Silica gel purification with 15-20% acetone: hexane elution yielded the desired product I-1b (7.96 g, 41%) as a waxy yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.53 (s, 1H), 7.58-7.39 (m, 4H), 6.05 (s, 1H), 4.49 (q, 2H), 1.42 (t, 3H); MS ( m / z) 314.1 (M + H); HPLC: retention time (RT): 2.4 minutes.

Preparation of the intermediate 3-chloro-2- (2-chloro-phenyl) -2,6-dihydro-pyrazolo [3,4-d] pyridazin-7-one (I-1c) :

A mixture of chloroaldehyde I-1b (13.5 g, 43.2 mmol) and t-butyl carbazate (5.7 g, 43.2 mmol) in absolute ethanol was refluxed at about 80 ° C. overnight. After cooling the reaction solution to room temperature, the resulting white precipitate was filtered, washed with cold ethanol and dried in vacuo to give the desired product I-1 as a white crystalline solid 18.0 g (97%) . ¹ H NMR (400MHz, CDCl ₃ ) δ8.48 (br s, 1H), 8.12 (br s, 1H), 7.55-7.39 (m, 4H), 4.42 (q, 2H), 1.51 (s, 9H), 1.39 (t, 3H); MS (m / z) 427.1 (M +); HPLC: retention time (RT): 2.8 minutes.

Preparation of intermediate 3-chloro-2- (2-chloro-phenyl) -2,6-dihydro-pyrazolo- [3,4-d] pyridazin-7-one (I-1d) :

A slurry of hydrazone I-1c (13.5 g, 31.6 mmol) in acetic acid (200 ml) was refluxed overnight. The reaction mixture was cooled to room temperature and the resulting precipitate was filtered and dried to give the desired product I-1d as a white solid, 8.28 g (93%). ¹ H NMR (400MHz, CD ₃ OD) δ8.48 (br s, 1H), 8.12 (br s, 1H), 7.55-7.39 (m, 4H), 4.42 (q, 2H), 1.51 (s, 9H) , 1.39 (t, 3H); MS (m / z) 281.1 (M +); HPLC: retention time (RT): 1.7 minutes.

Preparation of intermediate 2- (2-chloro-phenyl) -3- (4-fluoro-phenyl) -2,6-dihydro-pyrazolo [3,4-d] pyridazin-7-one (I-1e) :

Chloride I-1d (788.8, 2.81 mmol), p-fluorobenzeneboronic acid (550 mg, 3.93 mmol), palladium tetrakistriphenylphosphine (162 mg, 0.14 mmol) in 16: 1 toluene: ethanol (23.4 ml), and A slurry of potassium carbonate (2M, 4.2 ml, 3 eq) was heated under N ₂ at about 80 ° C. overnight and at −100 ° C. for 6 hours. The reaction was cooled to room temperature, diluted with 1N aqueous HCl (20 ml) and extracted with dichloromethane (3 × 20 ml). The dichloromethane extract was concentrated under vacuum resulting in precipitation. This solid was filtered to yield the desired product I-1e (846.9 mg, 89%) as a pale yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ9.80 (br s, 1H), 8.15 (s, 1H), 7.55-7.40 (m, 3H), 7.29 (m, 2H), 7.10 (t, 2H); MS (m / z) 341.2 (M +); HPLC: retention time (RT): 2.1 minutes.

Preparation of intermediate 7-chloro-2- (2-chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazine (I-1f) :

A slurry of pyridazinone I-1e (1104 mg, 3.24 mmol) in phosphorus oxychloride (15 ml) was heated at ˜100 ° C. for 3 hours. The reaction was cooled to room temperature and the solvent removed in vacuo to yield a sticky crude residue. Saturated sodium bicarbonate was added slowly, resulting in a chucky solid. While stirring vigorously, a uniformly suspended solid formed that was filtered, washed with water and dried under vacuum to give the desired product as a yellow solid (1120 mg, 96%) . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.25 (s, 1H), 7.7-7.30 (m, 7H); MS (m / z): 359.2 (M + H); Retention time (RT): 2.4 minutes .

Preparation of intermediate 2-chloro-N- (4-chloro-phenyl) -benzamidine (I-2a) :

To a solution of 4-chloro-phenylamine (18.2 g, 143 mmol) in toluene (550 ml), trimethylaluminum (2M in hexane, 100 ml, ₂₀₀ mmol) was added dropwise at 0 ° C. under N ₂ atmosphere. The reaction mixture was warmed to room temperature and stirred for 3.5 hours. A solution of 2-chlorobenzonitrile (23.6 g, 171 mmol) in toluene (140 ml) was added and the reaction mixture was heated at 80 ° C. for 17 hours, during which time it became homogeneous. The reaction mixture was cooled to room temperature and poured onto a slurry of silica gel in CHCl ₃ / methanol (2: 1). After filtration, the filter cake was washed with a mixture of CH ₂ Cl ₂ / MeOH (2: 1). The combined filtrate was concentrated in vacuo and the resulting yellow solid was triturated with hexane / ether (2: 1). Product I-2a (25.1 g, 66%) was used in the next reaction without further purification.

Preparation of intermediate 1- (4-chloro-phenyl) -2- (2-chloro-phenyl) -4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylic acid ethyl ester (I-2b) :

A mixture of 2-chloro-N- (4-chloro-phenyl) -benzamidine ( I-2a , 25.1 g, 95 mmol) and NaHCO ₃ (84 g, 189 mmol) in 2-propanol (473 ml) was added to 3-bromo-2 Treated with -oxo-propionic acid ethyl ester (14.3 ml, 22 g, 113 mmol). The reaction mixture was heated at 80 ° C. for 17 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue is diluted with CH ₂ Cl ₂ and the organic solution is washed with H ₂ O, dried over MgSO ₄ and concentrated in vacuo to give the product 1- (4-chloro-phenyl) -2- (2-chloro -Phenyl) -4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylic acid ethyl ester I-2b was produced as a dark red residue (36 g).

Preparation of 1- (4-chloro-phenyl) -2- (2-chloro-phenyl) -1H-imidazole-4-carboxylic acid ethyl ester (I-1c) :

Crude 1- (4-chloro-phenyl) -2- (2-chloro-phenyl) -4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylic acid obtained in the previous step in toluene (630 ml) Acid ethyl ester ( I-2b , 36 g, 94.7 mmol) and p-toluenesulfonic acid monohydrate (4.5 g, 24 mmol) were heated to reflux for 17 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in CH ₂ Cl ₂ and the organic solution was washed with H ₂ O, saturated aqueous NaHCO ₃ , and saturated aqueous NaCl, dried over MgSO ₄ and concentrated in vacuo. The crude residue was purified by silica gel plug filtration using a gradient solvent from 2% EtOAc / CH ₂ Cl ₂ to 10% EtOAc / CH ₂ Cl ₂ . Fractions containing this product were concentrated and the oily residue was diluted with 1: 3 EtOAc / hexanes (200 ml). After 1 h, a solid precipitated from the solution, which was collected by filtration and 1- (4-chloro-phenyl) -2- (2-chloro-phenyl) -1H-imidazole-4-carboxylic acid ethyl ester I -2c (18.63 g, 69.7%) was produced.

Preparation of 5-bromo-1- (4-chloro-phenyl) -2- (2-chloro-phenyl) -1H-imidazole-4-carboxylic acid ethyl ester (I-2d) :

Bromine (3.6 ml, 0.07 mol) was dissolved in 1- (4-chloro-phenyl) -2- (2-chloro-phenyl) -1H-imidazole-4-carboxylic acid ethyl ester ( I- 2c , 3.6 g, 0.01 mol) solution at room temperature. The reaction mixture was stirred for 17 hours, poured onto ice water and treated with 25% aqueous NaOH until the orange solution turned yellow. This aqueous solution was extracted with CH ₂ Cl ₂ (3 ×) and the combined extracts were dried and concentrated in vacuo to give the desired compound I-2d as an oil (4.7 g): + APCI MS ( M + 1) 441.1; ¹ H NMR (CD ₃ Cl) δ 1.41 (3H, t), 4.43 (2H, q), 7.08-7.12 (2H, m), 7.20-7.40 (7H, m).

Preparation of intermediate 1- (4-chloro-phenyl) -2- (2-chloro-phenyl) -5-formyl-1H-imidazole-4-carboxylic acid ethyl ester (I-2e) :

5-Bromo-1- (4-chloro-phenyl) -2- (2-chloro-phenyl) -1H-imidazole-4-carboxylic acid ethyl ester ( I-2d , 4.4 g, 0.01) in anhydrous THF (100 ml) To the solution of mmol) was slowly added tert-butyllithium (13 ml of a 1.7 M solution in pentane, 0.22 mol) at −78 ° C. After 1 hour, DMF (7.7 ml, 0.1 mL) was added dropwise. The reaction mixture was stirred at −78 ° C. for 2.5 hours, quenched with saturated aqueous NH ₄ Cl (10 ml), slowly warmed to room temperature and finally poured into saturated aqueous NaCl. The aqueous solution was extracted with Et ₂ 0 (3x) and the combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude residue was purified by flash chromatography using a solvent gradient of 1: 3 EtOAc / hexanes to 1: 1 EtOAc / hexanes to give the desired product I-2e as a pale yellow amorphous glass (2.0 g). : + APCl MS (M + 1) 389.2; ¹ H NMR (CD ₂ Cl ₂ ) δ1.41 (3H, t), 4.45 (2H, q), 7.09-7.14 (2H, m), 7.24-7.39 (7H m), 10.50 (1H, s).

Preparation of intermediate 1- (4-chloro-phenyl) -2- (2-chloro-phenyl) -5-hydrazonomethyl-1H-imidazole-4-carboxylic acid ethyl ester (I-2f) :

1- (4-Chloro-phenyl) -2- (2-chloro-phenyl) -5-formyl-1H-imidazole-4-carboxylic acid ethyl ester ( I-2e , 102mg, 0.26mmol), aqueous hydrazine hydrate A solution of (50% solution, 0.6 mmol) and glacial acetic acid (1 drop) was heated to reflux in toluene (3 ml) for 18 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO ₃ and CH ₂ Cl _2. The organic solution was dried and concentrated in vacuo. Purification using a 2 mm chromatotron plate and solvent gradient 1: 1 EtOAc / hexanes to 100% EtOAc yielded the desired product I-2f (R _f = 0.8, 100% EtOAc, 62 mg): APCI MS (M + 1) 403.1; ¹ H NMR (CD ₂ Cl ₂ ) δ1.40 (3H, t), 4.37 (2H, q), 5.60 (2H, br s), 7.10-7.14 (2H, m) , 7.21-7.25 (3H, m), 7.29-7.33 (3H, m), 8.40 (1H, s).

Preparation of intermediate 2- (2-chloro-phenyl) -1- (4-chloro-phenyl) -1,5-dihydro-imidazo [4,5-d] pyridazin-4-one (I-2g) :

1- (4-Chloro-phenyl) -2- (2-chloro-phenyl) -5-hydrazonomethyl-1H-imidazole-4-carboxylic acid ethyl ester ( I-2f , 54 mg, 0.134) in toluene (3 ml) mmol) and glacial acetic acid (1 drop) were heated at reflux for 18 h, at which point a white solid precipitated from the solution. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification of the crude residue by 1 mm chromatotron plate using 100% EtOAc as solvent gave the desired product ( I-2q ) as a white solid (22 mg): + APCI MS (M + 1) 357.1; ¹ H NMR (CD ₂ Cl ₂ ) δ 7.18-7.48 (8H, m), 8.01 (1H, s), 10.60 (1 H, s).

Preparation of the intermediate 4-chloro-2- (2-chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazine (I-2h) :

2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1,5-dihydro-imidazo [4,5-d] pyridazin-4-one in POCl ₃ (3 ml) ( I-2g , 22 mg, 0.062 mmol) was heated at reflux for 2.5 hours. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was dissolved in toluene and concentrated again. This procedure was repeated twice. The residue was then dissolved in CH ₂ Cl ₂ and H ₂ 0 was added. The pH of the aqueous solution was adjusted by adding saturated aqueous NaHCO ₃ until the pH was neutral (about 7). The CH ₂ Cl ₂ layer was separated and the aqueous solution was extracted with CH ₂ Cl ₂ (3 ×). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give I-2h as a pale yellow oil (22 mg): + APCI MS (M + 1) 375. 0 / 377.0 ¹ H NMR (CDCl ₃ ) δ 7.18-7.23 (2H, m), 7.35-7.48 (5H, m), 7.56-7.60 (1H, m), 9.22 (1H, s).

  Example 1 illustrates the preparation of pyrazolopyridazine analogs having general formulas (I) and (III).

Example 1 1- [2- (2-Chloro-phenyl) -3- (4-fluoro-phenyl) -2H-pyrazolo [3,4-d] pyridazin-7-yl] -4-isopropylamino-piperidine- Preparation of 4-carboxylic acid amide (1A-1) :

1-Benzyl-4-isopropylamino-4-piperidinecarboxamide (250 mg, 0.91 mmol) (commercially available from Aldrich Chemical, Milwaukee, WI), palladium on 10% charcoal (4 ml) in methanol (4 ml) A mixture of 30% by weight, 81 mg) and formic acid (5 mmol) was vigorously mixed overnight at room temperature. The reaction mixture was filtered through a celite pad and concentrated in vacuo to give the product 4-carbamoyl-4- (isopropylamino) piperidine (191 mg, 90%) as formate. A mixture of chloride I-1f (100 mg, 0.28 mmol), 4-carbamoyl-4- (isopropylamino) -piperidine (85 mg, 0.306 mmol) and triethylamine (0.13 ml, 0.92 mmol) in absolute ethanol (2 ml) Refluxed for 3 hours. The reaction mixture was cooled to room temperature, water was added and a solid precipitated. The filtrate was acidified and washed with ethyl acetate to remove impurities. The aqueous layer was basified with 1N NaOH, extracted with dichloromethane, dried and concentrated to give a crude solid. This was combined with the filtered solid and produced using short plug silica gel using 10% MeOH: EtOAc as eluent to give the desired product 1A-1 (46 mg, 30%) as a white solid. : ¹ H NMR (400MHz, CD ₃ OD) δ8.78 (s, 1H), 7.68-7.41 (m, 6H), 7.19-7.14 (t, 2H), 4.42 (br d, 2H), 4.16-4.13 (br t, 2H), 2.95-2.92 (m, 1H), 2.17-2.12 (m, 2H), 1.83-1.80 (br d, 2H), 1.10 (d, 6H); MS (m / z): 524.5 (M + H); Retention time (RT): 1.7 minutes.

The compounds listed in Tables 1A and 1B below were prepared using commercially available suitable starting materials, procedures well known to those skilled in the art, using procedures similar to those described above for the synthesis of Compound 1A-1. Or using starting materials prepared in a manner similar to that previously described for other intermediates. The compounds listed below were generally isolated as their free salts, then converted to their corresponding hydrochloride salts and then tested in vivo (when tested in vivo).

EtOH(1ml)中の4-クロロ-2-(2-クロロ-フェニル)-1-(4-クロロ-フェニル)-1H-イミダゾ[4,5-d]ピリダジン(I-2h, 11mg, 0.29mmol)、4-イソプロピルアミノ-ピペリジン-4-カルボン酸アミド(6mg, 0.032mmol)及びNEt₃(8μl, 0.06mmol)の溶液を、2時間還流加熱した。この反応混合物を室温に冷却し、真空で濃縮した。残渣を、エチレングリコール(1.5ml)で希釈し、及びNEt₃(8μl)を添加した。この反応混合物を、120℃で1.5時間、及び100℃で18時間加熱した。反応混合物を、室温に冷却し、H₂Oで希釈した。水溶液を、CH₂Cl₂(3x)で抽出し、一緒にした有機抽出物を、飽和したNaCl水溶液で洗浄し、乾燥し、真空で乾燥した。残渣を、10:1 CH₂Cl₂/MeOH(NH₃)を使用するクロマトトロンプレート(1mm)上で精製し、遊離アミン2A-1(8mg)を固形物として得た：+APCI MS (M+1) 523.9；¹H NMR (CD₃OD) δ1.08 (6H, d), 1.80-1.87 (2H, m), 2.16-2.25 (2H, m), 2.95-3.08 (1H, m), 4.18-4.30 (2H, m), 4.32-4.42 (2H, m)；7.30-7.70 (8H, m)。 Examples 2 and 3 illustrate the preparation of imidazo [4,5-d] pyridazine analogs having general formulas (II) and (IV).
Example 2
1- [2- (2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-isopropylamino-piperidine- Preparation of 4-carboxylic acid amide hydrochloride (2A-1) :

4-Chloro-2- (2-chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazine ( I-2h , 11mg, 0.29mmol) in EtOH (1ml) ), 4-isopropylamino-piperidine-4-carboxylic acid amide (6 mg, 0.032 mmol) and NEt ₃ (8 μl, 0.06 mmol) were heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethylene glycol (1.5 ml) and NEt ₃ (8 μl) was added. The reaction mixture was heated at 120 ° C. for 1.5 hours and at 100 ° C. for 18 hours. The reaction mixture was cooled to room temperature and diluted with H ₂ O. The aqueous solution was extracted with CH ₂ Cl ₂ (3 ×) and the combined organic extracts were washed with saturated aqueous NaCl, dried and dried in vacuo. The residue was purified on a chromatotron plate (1 mm) using 10: 1 CH ₂ Cl ₂ / MeOH (NH ₃ ) to give the free amine 2A-1 (8 mg) as a solid: + APCI MS (M +1) 523.9; ¹ H NMR (CD ₃ OD) δ1.08 (6H, d), 1.80-1.87 (2H, m), 2.16-2.25 (2H, m), 2.95-3.08 (1H, m), 4.18 -4.30 (2H, m), 4.32-4.42 (2H, m); 7.30-7.70 (8H, m).

1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-isopropylamino in CH ₂ Cl ₂ To a slurry of -piperidine-4-carboxylic acid amide ( 2A-1 , 8 mg) was added HCl (4M solution in dioxane, 8 μl). The reaction mixture was stirred for 0.25 hours and concentrated in vacuo to give 2A-1 hydrochloride as an amorphous solid.

The following compounds should be prepared using procedures similar to those described above for the preparation of compound 2A-1 , using commercially available suitable starting materials or starting materials prepared using procedures well known to those skilled in the art. I was able to:
1- [1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-isopropylamino-piperidine-4 -Carboxylic acid amides;
1- [1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-ethylamino-piperidine-4 -Carboxylic acid amides;
1- [1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-methylamino-piperidine-4 -Carboxylic acid amides;
1- [1- (4-Chloro-phenyl) -2- (2-fluoro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-methylamino-piperidine-4-carboxylic acid Acid amides;
1- [1- (4-Chloro-phenyl) -2- (2-fluoro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-ethylamino-piperidine-4-carboxylic acid Acid amides;
1- [1- (4-Chloro-phenyl) -2- (2-fluoro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -4-isopropylamino-piperidine-4-carboxylic acid Acid amides;
1- [1- (4-Chloro-phenyl) -2- (2-fluoro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-isopropylamino-azetidine-3-carbon Acid amides;
1- [1- (4-Chloro-phenyl) -2- (2-fluoro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-ethylamino-azetidine-3-carboxyl Acid amides;
1- [1- (4-Chloro-phenyl) -2- (2-fluoro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-methylamino-azetidine-3-carboxyl Acid amides;
1- [1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-isopropylamino-azetidine-3 -Carboxylic acid amides;
1- [1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-ethylamino-azetidine-3 -Carboxylic acid amides;
1- [1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-methylamino-azetidine-3 -Carboxylic acid amides;
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -7-methyl-1H-imidazo [4,5-d] pyridazin-4-yl] -3-isopropylamino-azetidine -3-carboxylic acid amide;
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -7-ethyl-1H-imidazo [4,5-d] pyridazin-4-yl] -3-isopropylamino-azetidine -3-carboxylic acid amide;
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-methylamino-pyrrolidine-3-carvone Acid amides;
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-ethylamino-pyrrolidine-3-carvone An acid amide; and
1- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -3-isopropylamino-pyrrolidine-3-carvone Acid amide.

Example 3
8- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -1-isopropyl-1,3,8- Preparation of triaza-spiro [4.5] decan-4-one hydrochloride (3A-1) :

4-Chloro-2- (2-chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazine ( I-2h , 11mg, 0.29mmol) in EtOH (1m) ), 1-isopropyl-1,3,8-triaza-spiro [4.5] decan-4-one (6 mg, 0.032 mmol) and NEt ₃ (8 μl, 0.06 mmol) were heated to reflux for 5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethylene glycol (1.5 ml) and NEt ₃ (8 μl) was added. The reaction mixture was heated at 120 ° C. for 2 hours and at 80 ° C. for 18 hours. The reaction mixture was cooled to room temperature and diluted with H ₂ 0. The aqueous solution was extracted with CH ₂ Cl ₂ (3 ×) and the combined organic extracts were washed with saturated aqueous NaCl, dried and concentrated in vacuo. The residue was purified on a chromatotron plate (1 mm) using 10: 1 CH ₂ Cl ₂ / MeOH (NH ₃ ) to yield the free amine 3A-1 (10 mg) as a solid: + APCI MS (M +1) 535.9; ¹ H NMR (CD ₂ Cl ₂ ) δ1.06 (6H, d), 1.82-1.98 (4H, m), 3.12-3.21 (1H, m), 4.18-4.25 (2H, m), 4.28 (3H, s), 4.84-4.92 (2H, m), 6.20 (1H, s), 7.18-7.23 (2H, m), 7.35-7.47 (5H, m), 7.51-7.55 (1H, m), 8.70 (1H, s).

8- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -1-isopropyl in CH ₂ Cl ₂ To a solution of 1,3,8-triaza-spiro [4.5] decan-4-one ( 3A-1 , 10 mg) was added HCl (4M solution in dioxane, 10 μl). The reaction mixture was stirred for 0.25 hours and concentrated in vacuo to yield 3A-1 hydrochloride as a white powder.

The following compounds should be prepared using procedures similar to those described above for the preparation of compound 3A-1 using commercially available suitable starting materials or starting materials prepared using procedures well known to those skilled in the art. I was able to:
2- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -5-methyl-2,5,7- Triaza-spiro [3.4] octane-8-one;
2- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -5-isopropyl-2,5,7- Triaza-spiro [3.4] octane-8-one;
2- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -1H-imidazo [4,5-d] pyridazin-4-yl] -5-isopropyl-7-methyl-2, 5,7-Triaza-spiro [3.4] octane-8-one;
2- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -7-methyl-1H-imidazo [4,5-d] pyridazin-4-yl] -5-isopropyl-7- Methyl-2,5,7-triaza-spiro [3.4] octane-8-one; and
2- [2- (2-Chloro-phenyl) -1- (4-chloro-phenyl) -7-methyl-1H-imidazo [4,5-d] pyridazin-4-yl] -5-isopropyl-2, 5,7-Triaza-spiro [3.4] octane-8-one.

Pharmacological Testing The usefulness of the compounds of the invention in the practice of the invention can be demonstrated by their activity in at least one protocol described below. The following initials are used in the protocol described below.
BSA-Bovine Serum Albumin
DMSO-dimethyl sulfoxide
EDTA-ethylenediaminetetraacetic acid
PBS-phosphate-buffered saline
EGTA-ethylene glycol bis (β-aminoethyl ether) N, N, N ', N'-tetraacetic acid
GDP-guanosine diphosphate
sc-subcutaneous
po-oral
ip-intraperitoneal
icv-intraventricular
iv-intravenous

[ ³ H] SR141716A-Radically labeled N- (piperidin-1-yl) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamide hydrochloride Salts were obtained from Amersham Biosciences, Piscataway, NJ.

[ ³ H] CP-55940-radiolabeled 5- (1,1-dimethylheptyl) -2- [5-hydroxy-2- (3-hydroxypropyl) -cyclohexyl] -phenol is available from NEN Life Science Products, Boston , Obtained from MA.

  AM251-N- (piperidin-1-yl) -1- (2,4-dichlorophenyl) -5- (4-iodophenyl) -4-methyl-1H-pyrazole-3-carboxamide is Tocris®, Obtained from Ellisville, MO.

Compounds 1A-1 to 1A-24 , 2A-1 and 3A-1 listed in the previous “Examples” section were tested in the CB-1 receptor binding assay described below. These compounds provided a range of binding activity from 0.2 nM to 21 nM. Selected compounds with activity <20 nM were then tested in the CB-1 GTPγ [ ³⁵ S] binding assay and CB-2 binding assay described below in the section “Biological Binding Assays”. The selected compounds were then tested in vivo using one or more functional assays described in the “Biological Functional Assays” section below.

In Vitro Biological Assay A bioassay system for determining CB-1 and CB-2 binding properties and pharmacological activity of cannabinoid receptor ligands is described by Roger G. Pertwee, “Pharmacology of Cannabinoid Receptor Ligands”, Current Medicinal Chemistry , 6,635-664 (1999) and WO 92/02640 (US patent application Ser. No. 07 / 564,075 filed Aug. 8, 1990, incorporated herein by reference). ing.

The following assay consists of [ ³ H] SR141716A (selective radiolabeled CB-1 ligand) and [ ³ H] 5- (1,1-dimethylheptyl) -2- [5-hydroxy-2- (3-hydroxy Designed to detect compounds that inhibit the binding of (propyl) -cyclohexyl] -phenol ([ ³ H] CP-55940; radiolabeled CB-1 / CB-2 ligand) to their respective receptors.

Rat CB-1 receptor binding protocol
PelFreeze brain (available from Pel Freeze Biologicals, Roger, AR) is cut and placed in tissue preparation buffer (5 mM Tris HCl, pH = 7.4 and 2 mM EDTA), processed at high speed with polytron and on ice. Left for 15 minutes. The homogenate was then centrifuged at 1,000 xg for 5 minutes at 4 ° C. The supernatant was collected and centrifuged at 100,000xG for 1 hour at 4 ° C. The pellet was then resuspended in 25 ml TME (25 nM Tris, pH = 7.4, 5 mM MgCl ₂ , and 1 mM EDTA) per brain used. A protein assay was performed and 200 μl of tissue, a total of 20 μg, was added to the assay solution.

Test compounds were diluted with drug buffer (0.5% BSA, 10% DMSO and TME) and then 25 μl was added to deep wells in polypropylene plates. [ ³ H] SR141716A was diluted in ligand buffer (0.5% BSA + TME) and 25 μl was added to the plate. Using the BCA protein assay, the appropriate tissue concentration was determined and then 200 μl of rat brain tissue was added to the plate at the appropriate concentration. These plates were covered and placed in a 20 ° C. incubator for 60 minutes. At the end of the incubation period, 250 μl of stop buffer (5% BSA + TME) was added to the reaction plate. The plates were then collected by Skatron on a GF / B filter mat pre-impregnated with BSA (5 mg / ml) + TME. Each filter was washed twice. The filter was dried overnight. In the morning, the filters were counted in a Wallac Betaplate ™ counter (available from PerkinElmer Life Sciences, Boston, Mass.).

Human CB-1 receptor binding protocol
Human embryonic kidney 293 (HEK293) cells transfected with CB-1 receptor cDNA (obtained from Dr. Debra Kendall, University of Connecticut) were homogenized with buffer (10 mM EDTA, 10 mM EGTA, 10 mM sodium bicarbonate, protease inhibitor). PH = 7.4) and homogenized with a Dounce homogenizer. The homogenate was then centrifuged at 1,000 xg for 5 minutes at 4 ° C. The supernatant was collected and centrifuged at 25,000xG for 20 minutes at 4 ° C. The pellet was then resuspended in 10 ml of homogenization buffer and recentrifuged at 25,000 × G for 20 minutes at 4 ° C. The final pellet was resuspended in 1 ml of TME (25 mM Tris buffer (pH = 7.4) containing 5 mM MgCl ₂ and 1 mM EDTA). A protein assay was performed and 200 μl of tissue, a total of 20 μg, was added to the assay solution.

Test compounds were diluted with drug buffer (0.5% BSA, 10% DMSO and TME) and then 25 μl was added to deep wells in polypropylene plates. [ ³ H] SR141716A was diluted in ligand buffer (0.5% BSA + TME) and 25 μl was added to the plate. These plates were covered and placed in a 30 ° C. incubator for 60 minutes. At the end of the incubation period, 250 μl of stop buffer (5% BSA + TME) was added to the reaction plate. The plates were then collected by Skatron on a GF / B filter mat pre-impregnated with BSA (5 mg / ml) + TME. Each filter was washed twice. The filter was dried overnight. In the morning, the filters were counted in a Wallac Betaplate ™ counter (available from PerkinElmer Life Sciences, Boston, Mass.).

CB-2 receptor binding protocol
Chinese hamster ovary-K1 (CHO-K1) cells transfected with CB-2 cDNA (obtained from Dr. Debra Kendall at the University of Connecticut) were washed with tissue preparation buffer (5 mM Tris-HCl buffer containing 2 mM EDTA ( pH = 7.4)), polytron treated at high speed, and left on ice for 15 minutes. The homogenate was then centrifuged at 1,000 xg for 5 minutes at 4 ° C. The supernatant was collected and centrifuged at 100,000xG for 1 hour at 4 ° C. The pellet was then resuspended in 1 ml of TME (25 mM Tris buffer (pH = 7.4) containing 5 mM MgCl ₂ and 1 mM EDTA) per brain used. A protein assay was performed and a total of 10 μg of 200 μl of tissue was added to the assay solution.

Test compounds were diluted with drug buffer (0.5% BSA, 10% DMSO and 80.5% TME), then 25 μl was added to deep wells in polypropylene plates. [ ³ H] CP-55940 was diluted in ligand buffer (0.5% BSA + 99.5% TME) and then 25 μl was added to each well at a concentration of 1 nM. Using the BCA protein assay, the appropriate tissue concentration was determined and 200 μl of the appropriate concentration of tissue was added to the plate. These plates were covered and placed in a 30 ° C. incubator for 60 minutes. At the end of the incubation period, 250 μl of stop buffer (5% BSA + TME) was added to the reaction plate. These plates were then collected by Skatron format on GF / B filter mats pre-impregnated with BSA (5 mg / ml) + TME. Each filter was washed twice. The filter was dried overnight. The filters were then counted in a Wallac Betaplate ™ counter (available from PerkinElmer Life Sciences, Boston, MA).

CB-1 GTPγ [ ³⁵ S] binding assay Membranes were prepared from CHO-K1 cells stably transfected with human CB-1 receptor cDNA. Membranes were prepared from cells as described in Bass et al., “Identification and characterization of novel somatostatin antagonists”, Molecular Pharmacology , 50, 709-715 (1996). GTPγ [ ³⁵ S] binding assay was performed using 50 mM Tris HCl (pH 7.4), 3 mM MgCl ₂ (pH 7.4), 10 mM MgCl ₂ , 20 mM EGTA, 100 mM NaCl, 30 μM GDP, 0.1 bovine serum albumin and the following protease inhibitors: Performed in duplicate in a 96-well FlashPlate ™ format using 100 pM GTP [ ³⁵ S] and 10 μg membrane / well in assay buffer composed of: 100 μg / ml bacitracin, 100 μg / ml benzamidine, 5 μg / ml aprotinin, 5 μg / ml leupeptin. This assay mixture was then incubated with increasing concentrations of antagonist (10 ⁻¹⁰ M to 10 ⁻⁵ M) for 10 minutes and challenged with the cannabinoid agonist CP-55940 (10 μM). The assay was performed at 30 ° C. for 1 hour. FlashPlates ™ were then centrifuged at 2000xg for 10 minutes. Thereafter, stimulation by GTPγ [ ³⁵ S] binding was quantified using Wallac Microbeta. EC ₅₀ calculations were performed using Graphpad's Prism ™. Reverse agonism was measured in the absence of agonist.

CB-1 FLIPR-based functional assay protocol CHO-K1 cells co-transfected with human CB-1 receptor cDNA (obtained from Dr. Debra Kendall, University of Connecticut) and promiscuous G-protein G16 are used for this assay. used. Cells were pre-seeded at 12,500 cells / well for 48 hours on collagen-coated 384-well black clear assay plates. Cells were incubated with 4 μM Fluo-4AM (Molecular Probes) for 1 hour in DMEM (Gibco) containing 2.5 mM probenecid and pluronic acid (0.04%). The plates were then washed 3 times with HEPES-buffered saline (containing probenecid; 2.5 mM) to remove excess dye. After 20 minutes, these plates were added individually to the FLIPR and the fluorescence level was continuously monitored over 80 seconds. Compound addition was performed simultaneously in all 384 wells 20 seconds after baseline. The assay was performed in triplicate and a 6-point concentration-response curve was generated. Antagonist compounds were subsequently challenged with 3 μM WIN 55,212-2 (agonist). Data was analyzed using Graph Pad Prism.

Inverse Agonist Detection Inverse agonist activity was measured using the following cyclic-AMP assay protocol using intact cells.

  Cells were seeded in 96-well plates at a seeding density of 10,000-14,000 cells / well and the concentration was 100 μl / well. These plates were incubated for 24 hours in a 37 ° C. incubator. The medium was removed and medium without serum (100 μl) was added. These plates were then incubated for 18 hours at 37 ° C.

  Serum-free medium containing 1 mM IBMX is added to each well, followed by 10 μl of test compound (1:10 stock solution (25 mM compound in DMSO) diluted in 50% DMSO / PBS), 0.1% BSA. Dilute 10X in PBS containing. After incubation for 20 minutes at 37 ° C., Forskolin 2 μM was added, followed by another 20 minutes incubation at 37 ° C. The medium was removed and 100 μl of 0.01N HCl was added followed by a 20 minute incubation at room temperature. Cell lysate (75 μl) was placed in a Flashplate along with 25 μl of assay buffer (available from NEN Life Science Products Boston, MA supplied with FlashPlate ™ cAMP assay kit). cAMP standards and cAMP tracer were added according to the kit protocol. The Flashplate was then incubated for 18 hours at 4 ° C. The contents of these wells were aspirated and counted with a scintillation counter.

In Vivo Biological Assays delta ⁹ - Cannabinoid agonists such as tetrahydrocannabinol (Δ ⁹ -THC) and CP-55940 have been found to affect the characteristic four behavior in mice, which are set It is referred to as Tetrad. For an explanation of these behaviors, see Smith, PB et al., “The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice”, J. Pharmacol. Exp. Ther. , 270 (1), 219-227 (1994) and See Wiley, J. et al., "Discriminative stimulus effects of anandamide in rats", Eur. J. Pharmacol. , 276 (1-2), 49-54 (1995). Reversal of these activities in the locomotor, catalepsy, hypothermia, and hot plate assays described below provides a screen for in vivo activity of CB-1 antagonists.

  All data was expressed as percent reversal from agonist alone using the following formula: (CP / agonist-vehicle / agonist) / (vehicle / vehicle-vehicle / agonist). Negative numbers indicate a synergistic effect of agonist activity or non-antagonist activity. A positive number indicates a reversal of activity for that particular test.

Locomotor Male ICR mice (n = 6) (17~19g, Charles River Laboratories, Inc., Wilmington, MA) were pretreated with test compounds (sc, po, ip, or icv). After 15 minutes, mice were challenged with CP-55940 (sc). Twenty-five minutes after agonist injection, mice were placed in a clear acrylic cage (431.8 cm x 20.9 cm x 20.3 cm) containing clean wood shavings. Subjects were allowed to explore the surroundings for a total of approximately 5 minutes, and activity was recorded by an infrared motion detector (available from Coulbourn Instruments ™, Allentown, PA) attached to the upper side of the cage. Data was collected on a computer and expressed as “movement units”.

Catalepsy male ICR mice (n = 6) (17-19 g upon arrival) were pretreated with test compounds (sc, po, ip, or icv). After 15 minutes, mice were challenged with CP-55940 (sc). Ninety minutes after injection, the mice were placed on a 6.5 cm steel ring attached to a ring stand at a height of approximately 12 inches. This ring was mounted in a horizontal direction, and the mouse was caught by the forelimbs and hindlimbs and suspended in the gap of the ring. The period during which the mouse was completely stationary (excluding respiratory motion) was recorded for 3 minutes.

  The data was expressed as a percentage of the rating of stationary. The rating was calculated by dividing the number of seconds the mouse was stationary by the total observed time and multiplying the result by 100. The% reversal by the agonist was then calculated.

Hypothermic male ICR mice (n = 5) (17-19 g upon arrival) were pretreated with the test compound (sc, po, ip, or icv). After 15 minutes, mice were challenged with the cannabinoid agonist CP-55940 (sc). Rectal body temperature was measured 65 minutes after agonist injection. This was measured by inserting a small thermostat probe approximately 2-2.5 cm into the rectum. The temperature was recorded at the nearest tenth of degree.

Hot Plate Assay Male ICR mice (n = 7) (17-19 g upon arrival) were pretreated with test compounds (sc, po, ip, or icv). After 15 minutes, mice were challenged with the cannabinoid agonist CP-55940 (sc). After 45 minutes, each mouse was tested for reversal of analgesia using a standard hot plate meter (Columbus Ni. Instruments). The hot plate was surrounded by a clear acrylic wall and was 10 "x10" x0.75 ". Latency time to kick, hind lick (lick) or light hit (flick), or jump from platform The timer was activated by the experimenter and each test was censored in 40 seconds The data is expressed as a percentage of agonist-induced reversal of analgesia. did.

Food intake The following screen was used to evaluate the efficacy of test compounds for inhibition of food intake in Sprague-Dawley rats after overnight fasting.
Male Sprague-Dawley rats were obtained from Charles River Laboratories, Inc. (Wilmington, Mass.). These rats were housed individually and fed a powdered diet. They were maintained on a 12 hour light / dark cycle with free access to food and water. Animals were acclimatized to the animal facility for a week prior to conducting the study. The test was completed in the light part of the cycle.

  To perform the food intake efficacy screening, rats were transferred to an individual test cage without food in the afternoon the day before the test, and the rats were fasted overnight. After an overnight fast, rats were administered vehicle or test compound the following morning. A known antagonist was administered as a positive control (3 mg / kg) and the control group received vehicle alone (no compound). Test compounds were administered in the range of 0.1-100 mg / kg depending on the compound. The standard vehicle was 0.5% (w / v) methylcellulose in water and the standard route of administration was oral. However, if necessary, different vehicles and routes of administration can be used to accommodate different compounds. Thirty minutes after dosing, food was provided to the rats and started with the Oxymax automatic food intake system (Columbus Instruments, Columbus, OH). Individual food intake was recorded continuously at 10-minute intervals over 2 hours. If necessary, food intake was recorded manually using an electric scale; food was weighed every 30 minutes after food was served up to a maximum of 4 hours. Compound efficacy was determined by comparing food intake patterns of compound-treated rats with vehicle and standard positive controls.

Alcohol intake The following protocol evaluates the effects of alcohol consumption in alcoholic (P) female rats (bred at Indiana University) with a history of excessive drinking. The following references provide a detailed description of P-rats: Li, T. -K. Et al., “Indiana selection studies on alcohol, related behaviors”, Development of Animal Models as Pharmacogenetic Tools (edited by McClearn E., Deitrich). RA and Erwin VG), Research Monograph, 6, 171-192 (1981) NIAAA, ADAMHA, Rockville, MD; Lumeng, L, et al., "New strains of rats with alcohol preference and nonpreference", Alcohol And Aldehyde Metabolizing Systems , 3, Academic Press, New York, 537-544 (1977); and Lumeng, L, et al., “Different sensitivities to ethanol in alcohol-preferring and-nonpreferring rats”, Pharmacol Biochem Behav .

  Female rats were allowed daily access to alcohol (10% v / v and water, 2 bottles selected) for 2 hours at the beginning of the dark cycle. These rats were maintained in a reverse cycle to facilitate experimenter interaction. These animals were initially assigned to 4 groups equal for alcohol consumption: 1 group—vehicle (n = 8); 2 groups—positive control (eg 5.6 mg / kg AM251; n = 8); 3 groups—low dose Test compound (n = 8); and Group 4-high dose test compound (n = 8). Test compounds were generally mixed in a volume of 1-2 ml / kg with a vehicle of 30% (w / v) β-cyclodextrin in distilled water. Vehicle injections were made for the first two days of the experiment for all groups. This was followed by 2 days of drug injection (to the appropriate group) and the last day of vehicle injection. On the day of drug injection, drug was given sc 30 minutes before the 2-hour alcohol access period. Alcohol intake in all animals was measured during the study period and a comparison was made between drug and vehicle-treated animals to determine the effect of these compounds on alcohol drinking behavior.

An additional drinking test was performed using female C57BI / 6 mice (Charles River). Several studies have shown that this strain of mice consumes alcohol easily with little or no manipulation (Middaugh et al., "Ethanol Consumption by C57BL / 6 Mice: Influence of Gender and Procedural Variables ", Alcohol , 17 (3), 175-183, 1999; Le et al.," Alcohol Consumption by C57BL / 6, BALA / c, and DBA / 2 Mice in a Limited Access Paradigm ", Pharmacology Biochemisrty and Behavior , 47 , 375-378,1994).

  For our purposes, mice arrived individually (17-19 g) upon arrival and were given unlimited powdered rat feed, water and a 10% (w / v) alcohol solution. After 2-3 weeks of unlimited access, water was limited to 20 hours, and alcohol was limited to only 2 hours of access daily. This was done so that the access period was the last two hours of the dark part of the light cycle.

  Once drinking behavior was stabilized, a test was conducted. Mice were considered stable when the average alcohol consumption for 3 days was ± 20% of the average for all 3 days. On the first day of testing, all mice received vehicle injections (sc or ip). Access to alcohol and water for 30-120 minutes after injection. Alcohol consumption for the day was calculated (g / kg) and the groups were assigned so that all groups had an unequivocal alcohol intake (n = 7-10). On days 2 and 3, mice were injected with vehicle or test compound and continued the same protocol as the previous day. On the fourth day, it was washed out and not injected. Data were analyzed using repeated measures ANOVA. Daily changes in water or alcohol consumption for the test were compared to the vehicle. A positive result would be interpreted that the compound can significantly reduce alcohol consumption but has no effect on water.

Oxygen consumption <br/> Method:
For whole body oxygen consumption, indirect calorimeters (obtained from Oxymax, Columbus Instruments, Columbus, OH) for male Sprague Dawley rats (identify if another rat strain or female rat is used) Use to measure. Rats (300-380 g body weight) are placed in the calorimeter chamber and the chamber is placed in the activity monitor. These tests are performed during the light cycle. Prior to the measurement of oxygen consumption, the rats are given a standard diet. Diet is not available when measuring oxygen consumption. Basic pre-dose oxygen consumption and ambulatory activity are measured every 10 minutes for 2.5 to 3 hours. At the end of the basic pre-dose period, the chamber is opened and the animal is given a single dose of compound (normal dose range is 0.001-10 mg / kg) by oral gavage (or other specified route of administration). I.e., sc, ip, iv). Drugs are prepared in methylcellulose, water or other specified vehicles (eg PEG 400, 30% β-cyclodextran and propylene glycol). Oxygen consumption and ambulatory activity are further measured every 10 minutes for 1-6 hours after administration.

  The Oxymax calorimeter software calculates oxygen consumption (ml / kg / hour) based on the difference in the air flow rate through the chamber and the oxygen content at the inlet and outlet. The activity monitor comprises 15 infrared light beams 1 inch apart in each axis, gait activity is recorded when two consecutive beams are broken, and the result is recorded as a count.

Except for periods of high ambulatory activity (gait activity count> 100) and excluding the first 5 values before administration and the first value after administration, resting oxygen consumption before and after administration, Calculated by taking the average of the O ₂ consumption values for 10 minutes. The change in oxygen consumption is recorded as a percentage (%) and is calculated by dividing post-administration resting oxygen consumption by pre-dose oxygen consumption and multiplying by 100. Experiments are typically performed on n = 4-6 rats and reported results are mean ± SEM.

Interpretation :
A> 10% increase in oxygen consumption is considered a positive result. In the past, vehicle-treated rats had no change in oxygen consumption from the pre-dose basis.

Claims (13)

Formula (I) or (II):

[Where
R ¹ is optionally substituted aryl or optionally substituted heteroaryl;
R ² is optionally substituted aryl or optionally substituted heteroaryl;
R ³ is hydrogen, (C ₁ -C ₄ ) alkyl, halo-substituted (C ₁ -C ₄ ) alkyl, or aryl;
R ⁴ is
(i) Formula (IA) or Formula (IB):

(Where
R ^4a is hydrogen or (C ₁ -C ₃ ) alkyl;
R ^4b and R ^{4b ′} are each independently hydrogen, cyano, hydroxy, amino, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, Acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)- , (C ₁ -C ₆ ) alkylamino-, ((C ₁ -C ₄ ) alkyl) ₂ amino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkyl Amino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3-6 membered partially or fully A chemical moiety selected from the group consisting of saturated carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents,
Or either R ^4b or R ^{4b ′} together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge;
X is a bond, —CH ₂ CH ₂ — or —C (R ^4c ) (R ^{4c ′} ) —, wherein R ^4c and R ^{4c ′} are each independently hydrogen, cyano, hydroxy, amino, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C _1- C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, di (C ₁ -C ₄ ) alkyl Amino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3- A chemical moiety selected from the group consisting of a 6-membered partially or fully saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein The moiety is optionally substituted with one or more substituents,
Or either R ^4c or R ^{4c ′} together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge;
Y is oxygen, sulfur, -C (O)-, or -C (R ^4d ) (R ^{4d '} )-, where R ^4d and R ^4d' are each independently hydrogen, cyano, hydroxy , Amino, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, ( C ₁ -C ₄₎ alkyl -NH-C (O) -, ((C 1 -C 4) _{alkyl) 2 NC (O) -,} (C 1 -C 6) alkylamino -, di (C ₁ -C ₄₎ alkylamino -, (C ₃ -C ₆₎ cycloalkylamino -, acylamino -, aryl (C ₁ -C ₄₎ alkylamino -, heteroaryl (C ₁ -C ₄₎ alkylamino -, aryl, heteroaryl A chemical moiety selected from the group consisting of a 3-6 membered partially or fully saturated heterocyclic ring, and a 3-6 membered partially or fully saturated carbocyclic ring, Wherein the moiety is optionally substituted with one or more substituents,
Or R ^4d and R ^{4d ′} together are a 3-6 membered partially or fully saturated heterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactam ring. Wherein the heterocyclic ring, the lactone ring and the lactam ring are optionally substituted by one or more substituents, and the lactone ring and the lactam ring are optionally selected from oxygen, nitrogen or sulfur Contain additional heteroatoms, or
Y is —NR ^{4d ″} —, where R ^{4d ″} is hydrogen or (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₃ ) alkylsulfonyl-, The group consisting of (C ₁ -C ₃ ) alkylaminosulfonyl-, di (C ₁ -C ₃ ) alkylaminosulfonyl-, acyl, (C ₁ -C ₆ ) alkyl-OC (O)-, aryl, and heteroaryl A chemical moiety selected from, wherein the moiety is optionally substituted with one or more substituents;
Z is a bond, —CH ₂ CH ₂ —, or —C (R ^4e ) (R ^{4e ′} ) —, wherein R ^4e and R ^{4e ′} are each independently hydrogen, cyano, hydroxy, amino , H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, di (C ₁ -C ₄ ) alkylamino -, (C ₃ -C ₆₎ cycloalkylamino -, acylamino -, aryl (C ₁ -C ₄₎ alkylamino -, heteroaryl (C ₁ -C ₄₎ alkylamino -, aryl, heteroaryl, 3 A chemical moiety selected from the group consisting of a -6 membered partially or fully saturated heterocyclic ring and a 3-6 membered partially or fully saturated carbocyclic ring, wherein The moiety is optionally substituted with one or more substituents,
Or either R ^4e or R ^{4e ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge; and
R ^4f and R ^{4f ′} are each independently hydrogen, cyano, hydroxy, amino, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, Acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)- , (C ₁ -C ₆ ) alkylamino-, di (C ₁ -C ₄ ) alkylamino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino- Heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3-6 membered partially or fully saturated Or a chemical moiety selected from the group consisting of carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents,
Alternatively, either R ^4f or R ^{4f ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge. )
A group having:
(ii) Formula (IC):

Wherein R ⁵ and R ⁶ are each independently hydrogen or (C ₁ -C ₄ ) alkyl, and R ⁷ is an optionally substituted (C ₁ -C ₄ ) alkyl-, or An optionally substituted 4-6 membered partially or fully saturated heterocyclic ring containing 1-2 heteroatoms independently selected from oxygen, sulfur, or nitrogen;
Or, R ⁵ and R ⁶ or R ⁵ and R ⁷ together represent a heteroatom independently selected from 5-6 membered lactone, 4-6 membered lactam, or oxygen, sulfur, or nitrogen. Form a 4-6 membered partially or fully saturated heterocycle containing 2 wherein the lactone, the lactam and the heterocycle are optionally substituted with one or more substituents. Yes. )
A group having
(iii) (C ₁ -C ₈ ) alkyl, aryl (C ₁ -C ₄ ) alkyl, partially or fully saturated (C ₃ -C ₈ ) cycloalkyl, hydroxy (C ₁ -C ₆ ) alkyl , (C ₁ -C ₃ ) alkoxy (C ₁ -C ₆ ) alkyl, heteroaryl (C ₁ -C ₃ ) alkyl, and at least one selected from the group consisting of fully or partially saturated heterocycles A chemical moiety is an amino group attached thereto, wherein the moiety is optionally substituted with one or more substituents. ]
Or a pharmaceutically acceptable salt thereof, a prodrug of the compound or the salt, or a solvate or hydrate of the compound, the salt or the prodrug. R ⁴ is the formula (IA):

[Wherein R ^4b and R ^{4b ′} are each independently hydrogen, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC ( O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, aryl, heteroaryl, 3-6 membered partial A chemical moiety selected from the group consisting of a fully or fully saturated heterocycle, and a 3-6 membered partially or fully saturated carbocyclic ring, wherein the moiety is optionally Substituted with one or more substituents,
Or R ^4b or R ^{4b ′} together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge;
X is a bond, —CH ₂ CH ₂ — or —C (R ^4c ) (R ^{4c ′} ) —, where R ^4c is hydrogen, cyano, hydroxy, amino, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C ( O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, ((C ₁ -C ₄ ) alkyl) ₂ amino-, (C _3- C ₆₎ cycloalkylamino -, acylamino -, aryl (C ₁ -C ₄₎ alkylamino -, heteroaryl (C ₁ -C ₄₎ alkylamino -, aryl, heteroaryl, 3-6 membered partially or A chemical moiety selected from the group consisting of fully saturated heterocycles and 3-6 membered partially or fully saturated carbocyclic rings, wherein the moiety is optionally one Or substituted with multiple substituents,
Or R ^4c together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge; and
R ^{4c ′} is hydrogen, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC (O) —, (C ₁ -C ₄ ) alkyl -NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3 A chemical moiety selected from the group consisting of -6-membered partially or fully saturated carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents ,
Or, R ^{4c 'is,} R ^4e, R ^4e' with, R ^4f or R ^{4f ',} forms a bond, a methylene bridge or an ethylene bridge;
Y is oxygen, sulfur, -C (O)-, or -C (R ^4d ) (R ^{4d '} )-, where R ^4d is hydrogen, cyano, hydroxy, amino, H ₂ NC (O) -, or (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, acyloxy, acyl, (C ₁ -C ₃₎ alkyl -OC (O) -, (C 1 -C 4) alkyl -NH -C (O) -, (( C 1 -C 4) _{alkyl) 2 NC (O) -,} (C 1 -C 6) alkylamino -, ((C ₁ -C ₄₎ alkyl) ₂ amino -, ( C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered moiety A chemical moiety selected from the group consisting of a partially or fully saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein the moiety is optional Substituted with one or more substituents, and
R ^{4d '} is hydrogen, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl -NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3 A chemical moiety selected from the group consisting of -6-membered partially or fully saturated carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents ,
Or R ^4d and R ^{4d ′} together are a 3-6 membered partially or fully saturated heterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactam ring. Wherein the heterocyclic ring, the lactone ring and the lactam ring are optionally substituted by one or more substituents, and the lactone ring and the lactam ring are optionally selected from oxygen, nitrogen or sulfur Contain additional heteroatoms, or
Y is —NR ^{4d ″} —, where R ^{4d ″} is hydrogen or (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₃ ) alkylsulfonyl-, The group consisting of (C ₁ -C ₃ ) alkylaminosulfonyl-, di (C ₁ -C ₃ ) alkylaminosulfonyl-, acyl, (C ₁ -C ₆ ) alkyl-OC (O)-, aryl, and heteroaryl A chemical moiety selected from, wherein the moiety is optionally substituted with one or more substituents;
Z is a bond, -CH ₂ CH _2- , or -C (R ^4e ) (R ^{4e '} )-, where R ^4e is hydrogen, cyano, hydroxy, amino, H ₂ NC (O)-, Or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, ((C ₁ -C ₄ ) alkyl) ₂ amino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered partially Or a chemical moiety selected from the group consisting of a fully saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein the moiety is optionally 1 Substituted with one or more substituents,
Or R ^4e together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge; and
R ^{4e '} is hydrogen, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl -NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3 A chemical moiety selected from the group consisting of -6-membered partially or fully saturated carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents ,
Or R ^{4e ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge; and
R ^4f and R ^{4f ′} are each independently hydrogen, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC (O) —, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, aryl, heteroaryl, 3-6 membered partially or completely A chemical moiety selected from the group consisting of a saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein the moiety is optionally one or more Or substituted with
Alternatively, either R ^4f or R ^{4f ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge. ]
2. The compound according to claim 1, having a group represented by the formula: or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound or the salt. R ¹ and R ² are each independently substituted phenyl;
R ^4b forms a bond, a methylene bridge or an ethylene bridge with hydrogen, optionally substituted (C ₁ -C ₃ ) alkyl, or R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} ;
R ^{4b ′} together with hydrogen, optionally substituted (C ₁ -C ₃ ) alkyl, or R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge;
R ^4f together with hydrogen, optionally substituted (C ₁ -C ₃ ) alkyl, or R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge;
R ^{4f ′} together with hydrogen, optionally substituted (C ₁ -C ₃ ) alkyl, or R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge,
3. The compound according to claim 2, a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound or the salt. X is -C (R ^4c ) (R ^{4c '} )-, wherein R ^4c and R ^4c' are each independently hydrogen, H ₂ NC (O)-, or (C ₁ -C ₆ ) Alkyl, (C ₁ -C ₄ ) alkyl-NH-C (O)-, or ((C ₁ -C ₄ ) alkyl) ₂ NC (O)- Wherein the moiety is optionally substituted with one or more substituents,
Or either R ^4c or R ^{4c ′} together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge;
Y is —NR ^{4d ″} where R ^{4d ″} is hydrogen or (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₃ ) alkylsulfonyl, ( C ₁ -C ₃ ) alkylaminosulfonyl, di (C ₁ -C ₃ ) alkylaminosulfonyl, acyl, (C ₁ -C ₆ ) alkyl-OC (O)-, aryl, and heteroaryl Wherein the moiety is optionally substituted with one or more substituents,
Z is -C (R ^4e ) (R ^{4e '} )-, wherein R ^4e and R ^4e' are each independently hydrogen, H ₂ NC (O)-, or (C ₁ -C ₆ ) Alkyl, (C ₁ -C ₄ ) alkyl-NH-C (O)-, or ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, wherein the moiety Is optionally substituted with one or more substituents,
Or either R ^4e or R ^{4e ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge,
4. The compound according to claim 2 or 3, a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound or the salt. Y is -C (R ^4d ) (R ^{4d '} )-, where R ^4d is hydrogen, cyano, hydroxy, amino, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C _1- C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, ((C ₁ -C ₄ ) alkyl) ₂ amino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino -, aryl (C ₁ -C ₄₎ alkylamino -, heteroaryl (C ₁ -C ₄₎ alkylamino -, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and A chemical moiety selected from the group consisting of 3-6 membered partially or fully saturated carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents; And
R ^{4d '} is hydrogen, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl -NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3 A chemical moiety selected from the group consisting of -6-membered partially or fully saturated carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents ,
Or R ^4d and R ^{4d ′} together are a 3-6 membered partially or fully saturated heterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactam ring. Wherein the heterocyclic ring, the lactone ring and the lactam ring are optionally substituted by one or more substituents, and the lactone ring and the lactam ring are optionally selected from oxygen, nitrogen or sulfur Containing additional heteroatoms,
4. The compound according to claim 2 or 3, a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound or the salt. X is a bond or —C (R ^4c ) (R ^{4c ′} ) —, where R ^4c and R ^{4c ′} are each hydrogen; and
Z is a bond or -C (R ^4e ) (R ^{4e '} )-, wherein R ^4e and R ^4e' are each hydrogen.
6. The compound according to claim 4 or 5, a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound or the salt. R ¹ and R ² each independently consist of halo, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, halo-substituted (C ₁ -C ₄ ) alkyl, and cyano The compound according to any one of claims 1 to 5, which is phenyl substituted with 1 to 3 substituents independently selected from the group, a pharmaceutically acceptable salt thereof, or the compound or Solvates or hydrates of the salts.   (1) The compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt of the compound, or a solvate or hydrate of the compound or the salt; (2) a pharmaceutically acceptable A pharmaceutical composition comprising an excipient, diluent, or carrier; and (3) an optional additional medicinal product.   9. The composition of claim 8, wherein the additional medicament is a nicotinic receptor partial agonist, opioid antagonist, dopaminergic drug, ADHD drug, or anti-obesity drug.   A method of treating a disease, symptom or disorder modulated by a cannabinoid receptor antagonist in an animal, comprising a therapeutically effective amount of the compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof. Or a solvate or hydrate of the compound or salt thereof to an animal in need of such treatment. A method of treating a disease, condition or disorder modulated by a cannabinoid receptor antagonist in an animal comprising:
(i) a first composition comprising a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient, diluent or carrier; and
(ii) such treatment comprises two separate pharmaceutical compositions, including a second composition, containing at least one additional pharmaceutical agent and a pharmaceutically acceptable excipient, diluent, or carrier. Said method comprising administering to an animal in need.   12. The method of claim 11, wherein the at least one additional pharmaceutical agent is a nicotinic receptor partial agonist, an opioid antagonist, a dopaminergic agent, an ADHD agent, or an anti-obesity agent. Formula (I) or (II) in the manufacture of a medicament for the treatment of a disease, condition or injury modulated by a cannabinoid receptor antagonist:

[Where
R ¹ is optionally substituted aryl or optionally substituted heteroaryl;
R ² is optionally substituted aryl or optionally substituted heteroaryl;
R ³ is hydrogen, (C ₁ -C ₄ ) alkyl, halo-substituted (C ₁ -C ₄ ) alkyl, or aryl;
R ⁴ is
(i) Formula (IA) or Formula (IB):

(Where
R ^4a is hydrogen or (C ₁ -C ₃ ) alkyl;
R ^4b and R ^{4b ′} are each independently hydrogen, cyano, hydroxy, amino, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, Acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)- , (C ₁ -C ₆ ) alkylamino-, ((C ₁ -C ₄ ) alkyl) ₂ amino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkyl Amino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3-6 membered partially or fully A chemical moiety selected from the group consisting of saturated carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents,
Or either R ^4b or R ^{4b ′} together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge;
X is a bond, —CH ₂ CH ₂ — or —C (R ^4c ) (R ^{4c ′} ) —, wherein R ^4c and R ^{4c ′} are each independently hydrogen, cyano, hydroxy, amino, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C _1- C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, di (C ₁ -C ₄ ) alkyl Amino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino-, heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3- A chemical moiety selected from the group consisting of a 6-membered partially or fully saturated heterocycle and a 3-6 membered partially or fully saturated carbocyclic ring, wherein The moiety is optionally substituted with one or more substituents,
Or either R ^4c or R ^{4c ′} together with R ^4e , R ^{4e ′} , R ^4f or R ^{4f ′} forms a bond, a methylene bridge or an ethylene bridge;
Y is oxygen, sulfur, -C (O)-, or -C (R ^4d ) (R ^{4d '} )-, where R ^4d and R ^4d' are each independently hydrogen, cyano, hydroxy , Amino, H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, ( C ₁ -C ₄₎ alkyl -NH-C (O) -, ((C 1 -C 4) _{alkyl) 2 NC (O) -,} (C 1 -C 6) alkylamino -, di (C ₁ -C ₄₎ alkylamino -, (C ₃ -C ₆₎ cycloalkylamino -, acylamino -, aryl (C ₁ -C ₄₎ alkylamino -, heteroaryl (C ₁ -C ₄₎ alkylamino -, aryl, heteroaryl A chemical moiety selected from the group consisting of a 3-6 membered partially or fully saturated heterocyclic ring, and a 3-6 membered partially or fully saturated carbocyclic ring, Wherein the moiety is optionally substituted with one or more substituents,
Or R ^4d and R ^{4d ′} together are a 3-6 membered partially or fully saturated carbocyclic ring, a 3-6 membered partially or fully saturated heterocyclic ring , A 5-6 membered lactone ring, or a 4-6 membered lactam ring, wherein the heterocyclic ring, the lactone ring, and the lactam ring are optionally substituted with one or more substituents; And the lactone ring and the lactam ring optionally contain an additional heteroatom selected from oxygen, nitrogen or sulfur, or
Y is —NR ^{4d ″} —, where R ^{4d ″} is hydrogen or (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₃ ) alkylsulfonyl-, The group consisting of (C ₁ -C ₃ ) alkylaminosulfonyl-, di (C ₁ -C ₃ ) alkylaminosulfonyl-, acyl, (C ₁ -C ₆ ) alkyl-OC (O)-, aryl, and heteroaryl A chemical moiety selected from, wherein the moiety is optionally substituted with one or more substituents;
Z is a bond, —CH ₂ CH ₂ —, or —C (R ^4e ) (R ^{4e ′} ) —, wherein R ^4e and R ^{4e ′} are each independently hydrogen, cyano, hydroxy, amino , H ₂ NC (O)-, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)-, (C ₁ -C ₆ ) alkylamino-, di (C ₁ -C ₄ ) alkylamino -, (C ₃ -C ₆₎ cycloalkylamino -, acylamino -, aryl (C ₁ -C ₄₎ alkylamino -, heteroaryl (C ₁ -C ₄₎ alkylamino -, aryl, heteroaryl, 3 A chemical moiety selected from the group consisting of a -6 membered partially or fully saturated heterocyclic ring and a 3-6 membered partially or fully saturated carbocyclic ring, wherein The moiety is optionally substituted with one or more substituents,
Or either R ^4e or R ^{4e ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge; and
R ^4f and R ^{4f ′} are each independently hydrogen, cyano, hydroxy, amino, H ₂ NC (O) —, or (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, acyloxy, Acyl, (C ₁ -C ₃ ) alkyl-OC (O)-, (C ₁ -C ₄ ) alkyl-NH-C (O)-, ((C ₁ -C ₄ ) alkyl) ₂ NC (O)- , (C ₁ -C ₆ ) alkylamino-, di (C ₁ -C ₄ ) alkylamino-, (C ₃ -C ₆ ) cycloalkylamino-, acylamino-, aryl (C ₁ -C ₄ ) alkylamino- Heteroaryl (C ₁ -C ₄ ) alkylamino-, aryl, heteroaryl, 3-6 membered partially or fully saturated heterocycle, and 3-6 membered partially or fully saturated Or a chemical moiety selected from the group consisting of carbocyclic rings, wherein the moiety is optionally substituted with one or more substituents,
Alternatively, either R ^4f or R ^{4f ′} together with R ^4b , R ^{4b ′} , R ^4c or R ^{4c ′} forms a bond, a methylene bridge or an ethylene bridge. )
A group having:
(ii) Formula (IC):

Wherein R ⁵ and R ⁶ are each independently hydrogen or (C ₁ -C ₄ ) alkyl, and R ⁷ is optionally substituted (C ₁ -C ₄ ) alkyl-, or An optionally substituted 4-6 membered partially or fully saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from oxygen, sulfur or nitrogen;
Or R ⁵ and R ⁶ or R ⁵ and R ⁷ together represent 1 or 6 heteroatoms independently selected from 5-6 membered lactones, 4-6 membered lactams, oxygen, sulfur or nitrogen. Forms a 4-6 membered partially or fully saturated heterocycle containing two, wherein the lactone, the lactam and the heterocycle are optionally substituted with one or more substituents . )
A group having:
(iii) (C ₁ -C ₈ ) alkyl, aryl (C ₁ -C ₄ ) alkyl, partially or fully saturated (C ₃ -C ₈ ) cycloalkyl, hydroxy (C ₁ -C ₆ ) alkyl , (C ₁ -C ₃ ) alkoxy (C ₁ -C ₆ ) alkyl, heteroaryl (C ₁ -C ₃ ) alkyl, and at least one selected from the group consisting of fully or partially saturated heterocycles A chemical moiety is an amino group attached thereto, wherein the moiety is optionally substituted with one or more substituents; or
(iv) hydroxy, (C ₁ -C ₆ ) alkoxy, amino, (C ₁ -C ₆ ) alkylamino, di ((C ₁ -C ₆ ) alkyl) amino (C ₁ -C ₃ ) alkylsulfonyl, (C ₁ -C ₃₎ alkyl sulfamyl, di ((C ₁ -C ₃₎ alkyl) sulfamyl, acyloxy, a partially or fully saturated heterocycle, and a partially or fully saturated carbocyclic A (C ₁ -C ₆ ) alkyl group to which is attached at least one chemical moiety selected from the group consisting of a ring, wherein the chemical moiety is by one or more substituents Are optionally substituted. ]
Or a pharmaceutically acceptable salt thereof, a prodrug of the compound or the salt, or a solvate or hydrate of the compound, the salt or the prodrug.